© 1999 American Heart Association, Inc.
Rapid Communication |
Enhanced Release of Prostaglandins Contributes to Flow-Induced Arteriolar Dilation in eNOS Knockout Mice
From the Departments of Physiology (D.S., A.H., A.K., G.K.) and Pathology (C.J. Smith, C.J. Stackpole, J.A.C.), New York Medical College, Valhalla, NY; Division of Hypertension and Vascular Research (E.G.S.), Henry Ford Hospital, Detroit, Mich.
Correspondence to Gabor Kaley, PhD, Department of Physiology, New York Medical College, Valhalla, NY 10595.
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Abstract—Nitric oxide and prostaglandins were shown to contribute to the endothelial mediation of flow-induced dilation of skeletal muscle arterioles of rats. Thus, we hypothesized that flow-induced dilation and its mediation are altered in gracilis muscle arterioles of mice deficient in the gene for endothelial nitric oxide synthase (eNOS-KO) compared with control wild-type (WT) mice. Gracilis muscle arterioles (
80 µm) of male mice were isolated, then cannulated and
pressurized in a vessel chamber. The increases in diameter elicited by
increases in perfusate flow from 0 to 10 µL/min were similar
in arterioles from eNOS-KO (n=28) and WT (n=22) mice (20 µm
at 10 µL/min flow). Removal of the endothelium
eliminated flow-induced dilations in vessels of both strains of mice.
N
-nitro-L-arginine (L-NNA,
10-4 mol/L) significantly inhibited flow-induced dilation
in arterioles of WT mice by 51% but had no effect on responses of
arterioles from eNOS-KO mice. Indomethacin (INDO,
10-5 mol/L) inhibited flow-induced dilation of WT mice by
49%, whereas it completely abolished this response in arterioles of
eNOS-KO mice. Simultaneous administration of INDO and L-NNA
eliminated flow-induced responses in arterioles of WT mice. Dilations
to carbaprostacyclin were similar at concentrations of
10-8 and 3x10-8 mol/L but decreased
significantly at 10-7 mol/L in arterioles of eNOS-KO
compared with those of WT mice. These findings demonstrate that,
despite the lack of nitric oxide mediation, flow-induced dilation is
close to normal in arterioles of eNOS-KO mice because of an enhanced
release of endothelial dilator
prostaglandins and suggest that this vascular adaptation
may contribute to the regulation of peripheral resistance
in eNOS-KO mice.
Key Words: transgenic mice • intraluminal flow • endothelium • nitric oxide • prostacyclin
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Considerable evidence demonstrates that endothelium-derived nitric oxide (NO) plays a critical role in the regulation of vascular tone.1 2 3 One of the important mechanisms through which NO release is controlled is by alterations in wall shear stress during changes in blood flow.3 4 Previous studies demonstrated that increases in perfusate flow elicit endothelium-dependent dilation of gracilis muscle arterioles, a response that is mediated by the combined release of NO and prostaglandins.5 It has also been demonstrated that reduced release of NO could lead to an enhanced arteriolar resistance, which may be involved in the pathogenesis of cardiovascular disorders, such as hypertension and atherosclerosis.6 7
The importance of the NO-related dilator mechanism is further underlined by studies showing a significant increase in blood pressure during systemic inhibition of nitric oxide synthase (NOS) with L-arginine analogs8 9 or when the gene encoding endothelial nitric oxide synthase (eNOS) is disrupted.10 11 Interestingly, however, there are quantitative differences in blood pressure in response to systemic administration of L-arginine analogs in wild-type (WT) mice compared with the level of blood pressure in eNOS knockout (KO) mice.10 This led us to hypothesize that the cardiovascular system adapts to an acute inhibition of NO synthesis in a manner that is different from that observed with a chronic lack of NO. Thus, it seemed to be of interest to elucidate the possible changes or adaptation of flow-sensitive vasomotor mechanisms regulating the tone of arterioles in mice that have a targeted disruption of the gene encoding eNOS. It can be assumed that because of the absence of NO release from endothelial cells, flow-induced dilation is severely attenuated in arterioles of eNOS-KO mice, compared with the same response of skeletal muscle arterioles of WT control mice. Alternatively, it can be hypothesized that endothelial cells adapt to the chronic lack of NO synthesis and maintain a normal or close to normal regulation of vascular tone by upregulation of other mechanisms. To our knowledge, there have been no studies published that have examined the mechanisms involved in endothelial responses to changes in flow in skeletal muscle arterioles of either normal or eNOS-deficient mice.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Animals
Heterozygous eNOS (+/-) mice, originally developed by Shesely et al11 were interbred to generate eNOS WT (+/+) and homozygous mutant (-/-) mice. Mice were genotyped by Southern analysis of DNA as described previously11 with the eNOS WT used as littermate controls for the eNOS-KO mice. All protocols were approved by the Institutional Animal Care and Use Committee of New York Medical College (NYMC) and conform to the current guidelines of the National Institutes of Health and the American Physiological Society for the use and care of laboratory animals. eNOS-KO and WT mice were bred in the Department of Comparative Medicine at NYMC. A total 28 male eNOS-KO mice and 22 male WT mice were used. Their average ages were 22.3±1.2 and 22.3±1.5 weeks, and their average body weights were 30.9±1.0 and 30.9±0.6 grams, respectively.
Experimental Setup
Experiments were conducted on isolated first-order gracilis
muscle arterioles of male eNOS-KO and WT mice. Mice were killed by
cervical dislocation. The dissection and isolation of vessels were
similar as described earlier for rats.5 A segment, about
1 mm long, of an arteriole was isolated and cannulated with 2
glass pipettes in a vessel chamber (1 mL in volume) and suffused (1
mL/min) with physiological salt solution, buffered
with NaHCO3 (24.0 mmol/L) and 5%
CO2 plus ambient air to maintain the pH at 7.4.
Intravascular pressure and temperature were maintained at 80
mm Hg and 37°C, respectively. Intraluminal flow was established by
changing proximal and distal pressures, controlled by 2 pressure-servo
systems (Living Systems Inc), to an equal degree but in opposite
directions without changing intravascular pressure.5 The
flow rate was measured by a ball flowmeter (FL-300, Omega) calibrated
to measure flow in a range of 0 to 100 µL/min. The diameter of
vessels, in various experimental conditions, was measured with an image
shearing monitor (IPM, model 907) and recorded with a chart
recorder (Graphtec Multicorder MC6625).
Experimental Procedures
Flow-Induced Dilation
Changes in diameter of arterioles in response to increases in
perfusate flow were studied. The vessels were equilibrated at
80 mm Hg of perfusion pressure for 1 hour, in a no-flow
condition, to develop spontaneous tone. Then, perfusate flow
was increased from 0 to 10 µL/min, in 2-µL/min steps. Each flow
step was maintained for 5 minutes to allow the vessels to reach a
stable diameter.
In the first series of experiments, flow-induced dilation was assessed before and after endothelial removal. Endothelial denudation was accomplished by injection of air into the vessel lumen, as described previously.5 The efficacy of removal of the endothelium and the function of smooth muscle were assessed by loss of arteriolar dilation to acetylcholine (10-8 mol/L) and maintained dilation to sodium nitroprusside (10-7 mol/L).
In the second series of experiments, endothelial
mediators responsible for flow-induced dilation were studied in
arterioles of both strains of mice. First, the role of
prostaglandins in flow-induced dilation was assessed. After
control flow-diameter curves were obtained,
indomethacin (INDO, 10-5 mol/L)
was added to the suffusion solution for 30 minutes to inhibit the
synthesis of prostaglandins. Then, the flow-diameter
relationships were reassessed. In separate experiments, the role of NO
in flow-induced dilation was assessed. After control responses were
obtained, vessels were incubated with
N-nitro-L-arginine
(L-NNA, 10-4 mol/L), an inhibitor of
NOS, for 30 minutes. Changes in diameter in response to step increases
in perfusate flow were again measured. In the presence of
L-NNA, additional INDO was given for 30 minutes before the experiments
were repeated.
Carbaprostacyclin-Induced Dilation
In separate experiments, arteriolar responses to
carbaprostacyclin (CP), a stable analog of prostacyclin, were
determined at 80 mm Hg pressure without intraluminal flow in the
2 groups of mice. CP (10-8 mol/L,
3x10-8 mol/L, and 10-7
mol/L) was administered to the vessel chamber in a cumulative manner,
and peak changes in diameter were recorded.
Passive Diameter
At the conclusion of each experiment, the suffusion solution was
changed to a Ca2+-free solution containing 1
mmol/L EGTA. Vessels were incubated for 10 minutes to reach maximal
diameter at 80 mm Hg perfusion pressure. The internal and
external diameters of the arteriole were then measured to calculate
wall thickness.
Chemicals
All chemicals were obtained from Sigma Chemical Co, except for
L-NNA, which was purchased from Aldrich Chemical Co, and CP, which
was obtained from Cayman Chemical. L-NNA (10-2
mol/L) was dissolved in saline with sonication. INDO and CP were
dissolved in DMSO (10-1 mol/L and
10-2 mol/L, respectively). Aliquots of CP were
stored in -20°C. All other solutions and drugs were prepared on the
day of the experiments by dilution with the suffusion
solution.
Calculations and Statistics
Passive diameter (internal) was used to assess the active
(basal) tone generated by arterioles in response to intravascular
pressure and to normalize the changes in diameter in response to
various stimuli in each vessel to compare the results between groups of
mice. Wall shear stress (WSS) was calculated as follows:
WSS=4
Q/
r3, where
is the viscosity of perfusate solution (0.007
poise, at 37°C), Q is the perfusate flow, and
r is the vessel radius. Wall thickness was calculated as the
difference between external and internal radii.
Data are mean±SEM. The number of mice used for each experimental protocol is denoted by n. When 2 or more vessels were studied from a mouse, responses were averaged. Both absolute and normalized data were evaluated. Statistical significance was calculated by repeated-measures ANOVA followed by Tukey/Kramer multiple-comparison test. Student's t test was also used, as appropriate. Significance level was taken at P<0.05.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The characteristics of arterioles isolated from the gracilis muscle of WT and eNOS-KO mice are shown in the Table
. Both basal and
passive diameters were significantly smaller in arterioles of eNOS-KO
mice compared with those of WT mice, whereas the basal tone, expressed
as a percentage of passive diameter, and wall thickness of arterioles
were not significantly different in eNOS-KO and WT mice.
|
In a total of 22 WT and 28 eNOS-KO mice, changes in diameter of
arterioles in response to step increases in intraluminal flow were
examined. Increasing flow from 0 to 10 µL/min elicited significant
increases in arteriolar diameter in both WT and eNOS-KO mice (Figure 1, top). The maximal changes in diameter
in response to increases in perfusate flow were similar
(21.9±1.6 and 20.1±1.2 µm at 10 µL/min, respectively). That
the dilation of arterioles from eNOS-KO and WT mice is nearly identical
can also be seen in the middle panel of Figure 1, in which the
normalized diameter as a function of perfusate flow is
depicted. Increases in flow elicited comparable increases in calculated
WSS in the 2 types of vessels (Figure 1, bottom).
|
Although removal of the endothelium did not affect
basal diameters, it completely eliminated flow-induced dilation in
vessels of both WT and eNOS-KO mice (Figure 2, top and bottom, respectively),
indicating that endothelial factors are responsible for
the mediation of this response. In separate experiments, the
endothelial mediators contributing to flow-induced
dilation of arterioles were investigated. The role of
prostaglandins in mediation of flow-induced dilation was
examined by comparing the responses before and after administration of
INDO. Basal arteriolar diameters were not significantly affected by
INDO, which, however, significantly inhibited flow-induced dilation by
49.4±10.4% (P<0.05) in arterioles of WT mice (Figure 3, top). In contrast, INDO abolished
flow-dependent dilation in vessels of eNOS-KO mice (Figure 3, bottom). In a separate group of experiments, the role of NO in
arteriolar responses to increases in flow was assessed by using L-NNA.
L-NNA did not significantly affect basal arteriolar diameter but
inhibited flow-induced dilation by 51.0±3.6% (P<0.05) in
arterioles of WT mice (Figure 4, top),
whereas it had no effect on the response in arterioles of eNOS-KO mice
(Figure 4, bottom). Additional administration of INDO completely
eliminated flow-induced dilation in arterioles of both WT and eNOS-KO
mice (Figure 4, top and bottom, respectively). These findings
demonstrate that both NO and prostaglandins mediate
flow-induced dilation in gracilis muscle arterioles of WT mice, whereas
prostaglandins alone contribute to the same degree of
dilation in arterioles of eNOS-deficient mice.
|
|
|
To characterize the reactivity of vascular smooth muscle to
prostaglandins, arteriolar responses to CP, a stable analog
of prostacyclin, were assessed. Figure 5
shows that there was no significant difference in vasodilator responses
to the lower concentrations of CP (10-8 mol/L
and 3x10-8 mol/L), but there was a significant
reduction in the response to the higher concentration of CP
(10-7 mol/L) in arterioles of eNOS-KO compared
with those of WT mice.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The new findings of the present study are as follows: (1) in male eNOS-KO mice, dilation of isolated skeletal muscle arterioles to flow/shear stress is close to normal, because of upregulation of endothelial prostanoid-mediated responses, and (2) in arterioles of WT mice, corelease of NO and prostaglandins mediates flow-induced dilation.
Endothelium-derived NO mediates dilation in response to physical stimuli, eg, shear stress,5 7 12 and to vasoactive agents, eg, acetylcholine, bradykinin, and substance P, in conduit vessels1 2 as well as microvessels.3 13 In vivo, the primary stimulus for the release of NO from the vascular endothelium is an increase in shear stress,3 4 5 a mechanism that has been shown to contribute importantly to the regulation of organ blood flow and peripheral resistance.3 Our previous studies showed that in arterioles of spontaneously hypertensive rats, endothelial NO release is reduced in response to shear stress, resulting in an impaired flow-dependent dilation,6 suggesting further that a strong association exists between NO release and peripheral resistance.6 After exercise training, on the other hand, the endothelial synthesis of NO14 15 in arterioles of rats and NOS gene expression16 in aorta of dogs is enhanced, eliciting greater arteriolar dilation to increases in shear stress.
Given that NO plays an important role in the mediation of shear stress–induced dilation, it was logical to hypothesize that in the absence of eNOS, arteriolar dilation to increases in shear stress is greatly diminished. However, the greater increase in blood pressure of WT mice administered L-NNA acutely, compared with the level of blood pressure found in eNOS-KO mice,10 led us to speculate that, perhaps as a result of an adaptive compensatory mechanism, flow-induced dilation is still maintained close to normal in vessels of eNOS-KO mice. To test this hypothesis, flow-induced dilation and the role of endothelial factors mediating this response were investigated in gracilis muscle arterioles of eNOS-KO and WT mice.
The average age and body weight of the 2 strains of mice were similar, and the vessels of the mice were carefully selected with respect to their anatomic location and branch order. Yet, the basal diameter and maximal passive diameter of gracilis arterioles of eNOS-KO mice were smaller than those of WT mice. The reason for this difference is not known, but it is likely to be related to the chronic lack of endothelial production of NO. In hypertensive rats, an experimental model associated with reduced endothelial synthesis of NO, the diameter of microvessels is reduced,17 a finding that is suggestive of an important role for NO in vascular remodeling.18 In the present study, there were no differences noted in the wall thickness of arterioles of the 2 strains of mice. Previous studies also showed no differences in lumen diameter and wall thickness of carotid18 and femoral19 arteries of eNOS-KO mice compared with those of WT mice. Interestingly, however, in small mesenteric arteries of eNOS-KO mice, an increased wall thickness was observed, an alteration that may favor an increase in peripheral resistance.
In the present study, the basal myogenic tone of vessels in the 2
strains of mice was not significantly different, indicating a similar
responsiveness to intraluminal pressure. This is of importance, given
that the level of myogenic tone can influence the magnitude of
flow/shear stress–dependent dilation.12 20 In
response to increases in intraluminal flow, arterioles of both strains
of mice exhibited substantial dilations. The actual changes in
diameter, the normalized dilator responses, and the level of shear
stress were similar in arterioles of WT and eNOS-KO mice (Figure 1
). These findings suggest that despite the absence of NO
synthesis in the endothelium of arterioles of eNOS-KO
mice, dilation of arterioles to increases in perfusate
flow/shear stress is preserved. We have also found that the
flow-dependent dilation of arterioles was entirely due to
endothelial factors, because removal of
endothelium eliminated the response in vessels of both
groups of mice (Figure 2). To study the
endothelial mediation of responses,
inhibitors, which interfere with the synthesis of NO and
prostaglandins, were used. In the absence of
perfusate flow, the basal diameter of arterioles was not
affected by 10-4 mol/L L-NNA or
10-5 mol/L INDO, inhibitor
concentrations that were shown to block completely the release of NO or
prostaglandins, respectively, in gracilis muscle arterioles
of the rat.5 Similar to these results, previous studies
found only a minimal basal release of NO in aorta10 and
pulmonary artery of eNOS knockout mice.21
As for the endothelial factors responsible for the
mediation of flow-induced responses in gracilis muscle arterioles of WT
mice, at 80 mm Hg of perfusion pressure, inhibition of either NO
or prostaglandin synthesis alone significantly reduced
arteriolar dilation to increases in perfusate flow by 50%
(Figures 3 and 4, top). Moreover, inhibition of the
synthesis of both mediators eliminated flow-induced dilation (Figure 4, top). These findings correspond to our previous report,
namely, that NO and prostaglandins are coreleased in rat
gracilis muscle arterioles in response to increases in flow and are
responsible for the ensuing vasodilation.5 In contrast, in
arterioles of eNOS-deficient mice, L-NNA had no effect, whereas
additional INDO completely inhibited the flow-dependent dilation
(Figures 3 and 4, bottom). Because previous studies
suggested that the presence of NO may interfere with the synthesis of
prostaglandins,22 23 24 one could surmise that a
chronic lack of NO in eNOS-KO mice may have elicited changes in the
function of the endothelium. That INDO alone completely
eliminated flow-induced dilation indicates that this response is solely
mediated by dilator prostaglandins. The results also
suggest that in the absence of mediation by endothelial
NO, an increased contribution of prostaglandins is
responsible for the close to normal flow-induced dilation in arterioles
of eNOS-KO mice.
Because previous studies indicated that NO donor–induced relaxations
are reduced when eNOS is overexpressed25 but are,
conversely, potentiated in eNOS-deficient mice,26 we aimed
to elucidate whether an enhanced sensitivity to or an enhanced release
of endothelial prostaglandins in response
to shear stress is responsible for the adaptation of arterioles in mice
deficient in the eNOS gene. To this end, arteriolar responses of the 2
strains of mice to a stable prostacyclin analog, CP, were contrasted.
The results show that at lower concentrations, CP elicited similar
dilations in vessels of the 2 groups of mice, whereas at higher
concentrations, responses of arterioles of eNOS-deficient mice were
reduced compared with those of WT mice (Figure 5). The reason
for the reduced sensitivity of arterioles to CP is not clear, but the
results, nevertheless, exclude the possibility that an enhanced
sensitivity of arteriolar smooth muscle to vasodilator
prostaglandins could account for the compensation and
suggest that an enhanced release of prostaglandins is
responsible for the maintenance of flow-dependent response in
eNOS-KO mice.
There are other published studies that suggest a physiological adaptation of the vasculature to the absence of the eNOS gene. A recent study showed similar reactive hyperemic responses of coronary vessels of eNOS-KO and WT mice.27 In this context, it has also been shown that the production of endothelium-derived hyperpolarizing factor and prostaglandins is enhanced in vessels of mice deficient in the eNOS gene. During a chronic absence of NO, these mediators may act as a protective mechanism in the maintenance of endothelial function, as has been documented in the mesenteric artery28 and coronary artery29 of eNOS-KO mice, as well as coronary vessels of dogs23 and carotid artery of rabbits.30
A possible underlying mechanism for the enhanced release of prostaglandins observed in the present study is suggested by previous reports showing an upregulation of the cyclooxygenase type 1 isoform (COX 1) in the endothelium of dog coronary artery31 and an overproduction of vasodilator prostaglandins in mesenteric arteries of rats, resulting in part from COX-2 expression,32 after chronic inhibition of eNOS. It is also possible that the intracellular mechanisms responsible for the compensation for the lack of NO in eNOS-deficient mice are vascular bed specific. For example, in gracilis muscle arterioles of male WT mice, the dilation to acetylcholine is mediated primarily by NO, whereas in vessels of eNOS-KO mice, the response to acetylcholine is mediated mainly by endothelium-derived hyperpolarizing factor.33 Responses to acetylcholine are mediated by neuronal NO in cerebral34 35 and prostaglandins in mesenteric arteries,36 and other, as yet unidentified, mediators in coronary artery29 of eNOS-KO mice. Thus, it is tempting to speculate that perhaps one or more redundant compensatory mechanisms become activated after selective gene deletion. Nevertheless, the investigation of these adaptive mechanisms may help to better understand the interaction among the various endothelium-derived vasoactive mediators to maintain normal vascular function.
In conclusion, the present study is the first to demonstrate that flow-induced dilation is mediated by both endothelial NO and prostaglandins in skeletal muscle arterioles of normal (WT) mice, whereas it is mediated exclusively by prostaglandins in those of eNOS-KO mice. This alteration may play a crucial role in the maintenance of shear stress–sensitive mechanisms in skeletal muscle arterioles and the regulation of peripheral resistance in eNOS-deficient mice.
|
Acknowledgments |
|---|
This study was supported by NIH Grants HL-43023 and HL-46813, AHA Grant 9930244N, and AHA New York State Affiliate Grant 9830015T. We appreciate the excellent secretarial assistance of Miriam Nunez and Mary Browne.
Received April 26, 1999; accepted June 11, 1999.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
1. Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980;228:373–376.
2. Palmer RMJ, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature. 1987;327:524–526.[Medline] [Order article via Infotrieve]
3. Koller A, Kaley G. Endothelial control of shear stress and resistance in skeletal muscle microcirculation. In: Bevan JA, Kaley G, Rubanyi GM, eds. Flow Dependent Regulation of Vascular Function. New York, NY: Oxford University Press; 1994:236–260.
4.
Koller A, Kaley G. Endothelium
regulates skeletal muscle microcirculation by a blood flow velocity
sensing mechanism. Am J Physiol. 1990;258:H916–H920.
5. Koller A, Sun D, Huang A, Kaley G. Corelease of nitric oxide and prostaglandins mediates flow-dependent dilation of rat gracilis muscle arterioles. Am J Physiol. 1994;266:H326–H332.
6.
Koller A, Huang A. Impaired nitric oxide mediated
flow-induced dilation in arterioles of spontaneously hypertensive rats.
Circ Res. 1994;74:416–421.
7.
Kuo L, Davis MJ, Cannon MS, Chilian WM.
Pathophysiological consequences of
atherosclerosis extend into the coronary
microcirculation: restoration of endothelium-dependent
responses by L-arginine. Circ Res. 1992;70:465–476.
8.
Rees DD, Palmer RJM, Moncada S. Role of
endothelium-derived nitric oxide in the regulation of
blood pressure. Proc Natl Acad Sci U S A. 1989;86:3375–3378.
9.
Pucci ML, Lin L, Nasjletti A. Pressor and renal
vasoconstrictor effects of
NG-nitro-L-arginine
as affected by blockade of pressor mechanisms mediated by the
sympathetic nervous system, angiotensin, prostanoids and
vasopressin. J Pharmacol Exp Ther. 1992;261:240–245.
10. Huang PL, Huang Z, Mashimo H, Bloch KD, Moskowitz MA, Bevan JA, Fishman MC. Hypertension in mice lacking the gene for endothelial NOS. Nature. 1995;377:239–242.[Medline] [Order article via Infotrieve]
11.
Shesely EG, Maeda N, Kim HS, Desai KM, Krege JH,
Laubach VE, Sherman PA, Sessa WC, Smithies O. Elevated blood pressure
in mice lacking endothelial nitric oxide synthase.
Proc Natl Acad Sci U S A. 1996;93:13176–13181.
12.
Kuo L, Chilian WM, Davis MJ. Interaction of
pressure- and flow-induced responses in porcine coronary
resistance vessels. Am J Physiol. 1991;261:H1706–H1715.
13.
Koller A, Seyedi N, Gerritsen ME, Kaley G. EDRF
released from microvascular endothelial cells dilates
arterioles in vivo. Am J Physiol. 1991;261:H128–H133.
14. Sun D, Huang A, Koller A, Kaley G. Adaptation of flow-induced dilation of arterioles to daily exercise. Microvasc Res. 1998;56:54–61.[Medline] [Order article via Infotrieve]
15.
Koller A, Huang A, Sun D, Kaley G. Exercise training
augments flow-dependent dilation in rat skeletal muscle arterioles:
role of endothelial nitric oxide and
prostaglandins. Circ Res. 1995;76:544–550.
16.
Sessa WC, Pritchard K, Seyedi N, Wang J, Hintze TH.
Chronic exercise in dogs increases coronary vascular nitric
oxide production and endothelial cell nitric
oxide synthase gene expression. Circ Res. 1994;74:349–353.
17.
Prewitt RL, Reilly CK, Wang DH. Pressure-flow curves
reflect arteriolar responses in perfused rat hindquarters.
Hypertension. 1994;23:223–228.
18. Rudic RD, Shesely EG, Maeda N, Smithies O, Segal SS, Sessa WC. Direct evidence for the importance of endothelium-derived nitric oxide in vascular remodeling. J Clin Invest. 1998;101:731–736.[Medline] [Order article via Infotrieve]
19. Moroi M, Zhang L, Yasuda T, Virmani R, Gold HK, Fishman MC, Huang PL. Interaction of genetic deficiency of endothelial nitric oxide, gender, and pregnancy in vascular response to injury in mice. J Clin Invest. 1998;101:1225–1232.[Medline] [Order article via Infotrieve]
20. Sun D, Huang A, Koller A, Kaley G. Flow-dependent dilation and myogenic constriction interact to establish the resistance of skeletal muscle arterioles. Microcirculation. 1995;2:289–295.[Medline] [Order article via Infotrieve]
21.
Steudel W, Ichinose F, Huang PL, Hurford WE, Jones RC,
Bevan JA, Fishman MC, Zapol WM. Pulmonary vasoconstriction and
hypertension in mice with targeted disruption of the
endothelial nitric oxide synthase (NOS 3) gene.
Circ Res. 1997;81:34–41.
22. Doni MG, Whittle BJR, Palmer RMJ, Moncada S. Actions of nitric oxide on the release of prostacyclin from bovine endothelial cells in culture. Eur J Pharmacol. 1988;151:19–25.[Medline] [Order article via Infotrieve]
23.
Puybasset L, Bea ML, Ghaleh B, Giudicelli JF, Berdeaux
A. Coronary and systemic hemodynamic effects of
sustained inhibition of nitric oxide synthesis in conscious dogs:
evidence for cross talk between nitric oxide and
cyclooxygenase in coronary vessels.
Circ Res. 1996;79:343–357.
24.
Danielson LA, Conrad KP. Prostaglandins maintain renal
vasodilation and hyperfiltration during chronic nitric oxide synthase
blockade in conscious pregnant rats. Circ Res. 1996;79:1161–1166.
25. Ohashi Y, Kawashima S, Hirata K, Yamashita T, Ishuda T, Inoue N, Sakoda T, Kurihara H, Yazaki Y, Yokoyama M. Hypotension and reduced nitric oxide-elicited vasorelaxation in transgenic mice overexpressing endothelial nitric oxide synthase. J Clin Invest. 1998;102:2061–2071.[Medline] [Order article via Infotrieve]
26.
Faraci FM, Sigmund CD, Shesely EG, Maeda N, Heistad DD.
Responses of carotid artery in mice deficient in expression of the gene
for endothelial NO synthase. Am J
Physiol. 1998;274:H564–H570.
27.
Gödecke A, Decking UKM, Ding Z, Hirchenhain J,
Bidmon HJ, Gödecke S, Schrader J. Coronary
hemodynamics in endothelial NO synthase
knockout mice. Circ Res. 1998;82:186–194.
28.
Thorin E, Huang PL, Fishman MC, Bevan JA. Nitric oxide
inhibits 
2-adrenoceptor–mediated
endothelium-dependent vasodilation. Circ
Res. 1998;82:1323–1329.
29. Lamping K, Nuno D, Shesely EG, Maeda N, Faraci F. Preserved responses to acetylcholine in coronary arteries from endothelial nitric oxide synthase deficient mice. FASEB J. 1998;12:A978. Abstract.
30.
Bauersacha J, Popp R, Hecker M, Sauer E, Fleming I,
Busse R. Nitric oxide attenuates the release of
endothelium-derived hyperpolarizing factor.
Circulation. 1996;94:3341–3347.
31. Beverelli F, Bea ML, Puybasset L, Giudicelli JF, Berdeaux A. Chronic inhibition of NOS enhances the production of prostacyclin in coronary arteries through upregulation of the cyclo-oxygenase type 1 isoform. Fundam Clin Pharmacol. 1997;11:252–259.[Medline] [Order article via Infotrieve]
32. Henrion D, Dechaux E, Dowell FJ, Maclour J, Samuel JL, Levy BI, Michel JB. Alteration of flow-induced dilatation in mesenteric resistance arterioles of L-NAME treated rats and its partial association with induction of cyclo-oxygenase-2. Br J Pharmacol. 1997;121:83–90.[Medline] [Order article via Infotrieve]
33. Huang A, Sun D, Smith CJ, Stackpole C, Shesely EG, Koller A, Kaley G. Attenuated acetylcholine (ACh)-induced dilation in arterioles of eNOS knockout mice. FASEB J. 1999;13:A1066. Abstract 796.5.
34.
Meng W, Ma J, Ayata C, Hara H, Huang PL, Fishman MC,
Moskowitz MA. ACh dilates pial arterioles in
endothelial and neuronal NOS knockout mice by
NO-dependent mechanisms. Am J Physiol. 1996;271:H1145–H1150.
35.
Meng W, Ayata C, Waeber C, Huang PL, Fishman MC,
Moskowitz MA. Neuronal NOSc-GMP-dependent ACh-induced relaxation in
pial arterioles of endothelial NOS knockout mice.
Am J Physiol. 1998;274:H411–H494.
36. Chataigneau T, Félétou M, Huang PL, Fishman MC, Duhalt J, Vanhoutte PM. Acetylcholine-induced relaxation in blood vessels from endothelial nitric oxide synthase knockout mice. Br J Pharmacol. 1999;126:219–226.[Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  B. J. Wong, G. Simmons, C. Bopp, J. Yeboah, D. P. Casey, C. Austin, H. Tanaka, A. E. DeVan, J. N. Barnes, G. Atkinson, et al. Commentaries on Viewpoint: Pick your Poiseuille: Normalizing the shear stimulus in studies of flow-mediated dilation J Appl Physiol, October 1, 2009; 107(4): 1360 - 1365. [Full Text] [PDF]
|
|
|
|
 |
|
 M Guazzi and R Arena Endothelial dysfunction and pathophysiological correlates in atrial fibrillation Heart, January 15, 2009; 95(2): 102 - 106. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Dhindsa, S. M. Sommerlad, A. E. DeVan, J. N. Barnes, J. Sugawara, O. Ley, and H. Tanaka Interrelationships among noninvasive measures of postischemic macro- and microvascular reactivity J Appl Physiol, August 1, 2008; 105(2): 427 - 432. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. C. Looft-Wilson, B. S. Ashley, J. E. Billig, M. R. Wolfert, L. A. Ambrecht, and S. E. Bearden Chronic diet-induced hyperhomocysteinemia impairs eNOS regulation in mouse mesenteric arteries Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2008; 295(1): R59 - R66. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. J Dietze and E. J Henriksen Review: Angiotensin-converting enzyme in skeletal muscle: sentinel of blood pressure control and glucose homeostasis Journal of Renin-Angiotensin-Aldosterone System, June 1, 2008; 9(2): 75 - 88. [Abstract] [PDF]
|
|
|
|
|
|
S. E. Bearden Advancing age produces sex differences in vasomotor kinetics during and after skeletal muscle contraction Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2007; 293(3): R1274 - R1279. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. D. van Deel, D. Merkus, R. van Haperen, M. C. de Waard, R. de Crom, and D. J. Duncker Vasomotor control in mice overexpressing human endothelial nitric oxide synthase Am J Physiol Heart Circ Physiol, August 1, 2007; 293(2): H1144 - H1153. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. G. Ingram, S. C. Newcomer, E. M. Price, K. E. Eklund, R. M. McAllister, and M. H. Laughlin Chronic nitric oxide synthase inhibition blunts endothelium-dependent function of conduit coronary arteries, not arterioles Am J Physiol Heart Circ Physiol, June 1, 2007; 292(6): H2798 - H2808. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Focardi, G. M. Dick, A. Picchi, C. Zhang, and W. M. Chilian Restoration of coronary endothelial function in obese Zucker rats by a low-carbohydrate diet Am J Physiol Heart Circ Physiol, May 1, 2007; 292(5): H2093 - H2099. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Adlam, J. K. Bendall, J. P. De Bono, N. J. Alp, J. Khoo, T. Nicoli, M. Yokoyama, S. Kawashima, and K. M. Channon Cardiovascular Control: Relationships between nitric oxide-mediated endothelial function, eNOS coupling and blood pressure revealed by eNOS-GTP cyclohydrolase 1 double transgenic mice Exp Physiol, January 1, 2007; 92(1): 119 - 126. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Sun, H. Liu, C. Yan, A. Jacobson, C. Ojaimi, A. Huang, and G. Kaley COX-2 contributes to the maintenance of flow-induced dilation in arterioles of eNOS-knockout mice Am J Physiol Heart Circ Physiol, September 1, 2006; 291(3): H1429 - H1435. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Kohler, W.-T. Heyken, P. Heinau, R. Schubert, H. Si, M. Kacik, C. Busch, I. Grgic, T. Maier, and J. Hoyer Evidence for a Functional Role of Endothelial Transient Receptor Potential V4 in Shear Stress-Induced Vasodilatation Arterioscler Thromb Vasc Biol, July 1, 2006; 26(7): 1495 - 1502. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. S. Deeb, H. Shen, C. Gamss, T. Gavrilova, B. D. Summers, R. Kraemer, G. Hao, S. S. Gross, M. Laine, N. Maeda, et al. Inducible Nitric Oxide Synthase Mediates Prostaglandin H2 Synthase Nitration and Suppresses Eicosanoid Production Am. J. Pathol., January 1, 2006; 168(1): 349 - 362. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. A. Hatoum, K. M. Gauthier, D. G. Binion, H. Miura, G. Telford, M. F. Otterson, W. B. Campbell, and D. D. Gutterman Novel Mechanism of Vasodilation in Inflammatory Bowel Disease Arterioscler Thromb Vasc Biol, November 1, 2005; 25(11): 2355 - 2361. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Ojaimi, W. Li, S. Kinugawa, H. Post, A. Csiszar, P. Pacher, G. Kaley, and T. H. Hintze Transcriptional basis for exercise limitation in male eNOS-knockout mice with age: heart failure and the fetal phenotype Am J Physiol Heart Circ Physiol, October 1, 2005; 289(4): H1399 - H1407. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Zhou, S. Varadharaj, X. Zhao, N. Parinandi, N. A. Flavahan, and J. L. Zweier Acetylcholine causes endothelium-dependent contraction of mouse arteries Am J Physiol Heart Circ Physiol, September 1, 2005; 289(3): H1027 - H1032. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Huang, D. Sun, C. Yan, J. R. Falck, and G. Kaley Contribution of 20-HETE to Augmented Myogenic Constriction in Coronary Arteries of Endothelial NO Synthase Knockout Mice Hypertension, September 1, 2005; 46(3): 607 - 613. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. A. Miller, A. A. Hislop, P. J. Vallance, and S. G. Haworth Deletion of the eNOS gene has a greater impact on the pulmonary circulation of male than female mice Am J Physiol Lung Cell Mol Physiol, August 1, 2005; 289(2): L299 - L366. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Milkiewicz, O. Hudlicka, M. D. Brown, and H. Silgram Nitric oxide, VEGF, and VEGFR-2: interactions in activity-induced angiogenesis in rat skeletal muscle Am J Physiol Heart Circ Physiol, July 1, 2005; 289(1): H336 - H343. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. D. Rudic, D. Brinster, Y. Cheng, S. Fries, W.-L. Song, S. Austin, T. M. Coffman, and G. A. FitzGerald COX-2-Derived Prostacyclin Modulates Vascular Remodeling Circ. Res., June 24, 2005; 96(12): 1240 - 1247. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. L. Moens, I. Goovaerts, M. J. Claeys, and C. J. Vrints Flow-Mediated Vasodilation: A Diagnostic Instrument, or an Experimental Tool? Chest, June 1, 2005; 127(6): 2254 - 2263. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D Tousoulis, C Antoniades, and C Stefanadis Evaluating endothelial function in humans: a guide to invasive and non-invasive techniques Heart, April 1, 2005; 91(4): 553 - 558. [Full Text] [PDF]
|
|
|
|
|
|
A. Huang, D. Sun, A. Jacobson, M. A. Carroll, J. R. Falck, and G. Kaley Epoxyeicosatrienoic Acids Are Released to Mediate Shear Stress-Dependent Hyperpolarization of Arteriolar Smooth Muscle Circ. Res., February 18, 2005; 96(3): 376 - 383. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. S. Scotland, M. Madhani, S. Chauhan, S. Moncada, J. Andresen, H. Nilsson, A. J. Hobbs, and A. Ahluwalia Investigation of Vascular Responses in Endothelial Nitric Oxide Synthase/Cyclooxygenase-1 Double-Knockout Mice: Key Role for Endothelium-Derived Hyperpolarizing Factor in the Regulation of Blood Pressure in Vivo Circulation, February 15, 2005; 111(6): 796 - 803. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. D. Katz, K. Hryniewicz, I. Hriljac, K. Balidemaj, C. Dimayuga, A. Hudaihed, and A. Yasskiy Vascular Endothelial Dysfunction and Mortality Risk in Patients With Chronic Heart Failure Circulation, January 25, 2005; 111(3): 310 - 314. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Bucci, F. Roviezzo, I. Posadas, J. Yu, L. Parente, W. C. Sessa, L. J. Ignarro, and G. Cirino Endothelial nitric oxide synthase activation is critical for vascular leakage during acute inflammation in vivo PNAS, January 18, 2005; 102(3): 904 - 908. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. A. Dinenno and M. J. Joyner Combined NO and PG inhibition augments {alpha}-adrenergic vasoconstriction in contracting human skeletal muscle Am J Physiol Heart Circ Physiol, December 1, 2004; 287(6): H2576 - H2584. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Fazel, R. D. Weisel, and S. Verma A novel technique to assess flow-mediated vasodilation J. Am. Coll. Cardiol., October 6, 2004; 44(7): 1478 - 1480. [Full Text] [PDF]
|
|
|
|
|
|
A. Y. Chong, A. D. Blann, J. Patel, B. Freestone, E. Hughes, and G. Y.H. Lip Endothelial Dysfunction and Damage in Congestive Heart Failure: Relation of Flow-Mediated Dilation to Circulating Endothelial Cells, Plasma Indexes of Endothelial Damage, and Brain Natriuretic Peptide Circulation, September 28, 2004; 110(13): 1794 - 1798. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Li, G. G. Geary, R. J. Gonzales, D. N. Krause, and S. P. Duckles Effect of estrogen on cerebrovascular prostaglandins is amplified in mice with dysfunctional NOS Am J Physiol Heart Circ Physiol, August 1, 2004; 287(2): H588 - H594. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Merkus, B. Houweling, A. Zarbanoui, and D. J. Duncker Interaction between prostanoids and nitric oxide in regulation of systemic, pulmonary, and coronary vascular tone in exercising swine Am J Physiol Heart Circ Physiol, March 1, 2004; 286(3): H1114 - H1123. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. A. Imadojemu, L. I. Sinoway, and U. A. Leuenberger Vascular Dysfunction in Sleep Apnea: A Reversible Link to Cardiovascular Disease? Am. J. Respir. Crit. Care Med., February 1, 2004; 169(3): 328 - 329. [Full Text] [PDF]
|
|
|
|
|
|
H. L. Xu, R. A. Santizo, V. L. Baughman, and D. A. Pelligrino Nascent EDHF-mediated cerebral vasodilation in ovariectomized rats is not induced by eNOS dysfunction Am J Physiol Heart Circ Physiol, November 1, 2003; 285(5): H2045 - H2053. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A.-Y. Chong, A.D. Blann, and G.Y.H. Lip Assessment of endothelial damage and dysfunction: observations in relation to heart failure QJM, April 1, 2003; 96(4): 253 - 267. [Full Text] [PDF]
|
|
|
|
|
|
P. A. Ortiz and J. L. Garvin Cardiovascular and renal control in NOS-deficient mouse models Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2003; 284(3): R628 - R638. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Iwakiri, G. Cadelina, W. C. Sessa, and R. J. Groszmann Mice with targeted deletion of eNOS develop hyperdynamic circulation associated with portal hypertension Am J Physiol Gastrointest Liver Physiol, November 1, 2002; 283(5): G1074 - G1081. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. H. Beierwaltes Cyclooxygenase-2 products compensate for inhibition of nitric oxide regulation of renal perfusion Am J Physiol Renal Physiol, July 1, 2002; 283(1): F68 - F72. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Huang, D. Sun, E. G. Shesely, E. M. Levee, A. Koller, and G. Kaley Neuronal NOS-dependent dilation to flow in coronary arteries of male eNOS-KO mice Am J Physiol Heart Circ Physiol, February 1, 2002; 282(2): H429 - H436. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. C. Corretti, T. J. Anderson, E. J. Benjamin, D. Celermajer, F. Charbonneau, M. A. Creager, J. Deanfield, H. Drexler, M. Gerhard-Herman, D. Herrington, et al. Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: A report of the International Brachial Artery Reactivity Task Force J. Am. Coll. Cardiol., January 16, 2002; 39(2): 257 - 265. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Huang, Y. Wu, D. Sun, A. Koller, and G. Kaley Effect of estrogen on flow-induced dilation in NO deficiency: role of prostaglandins and EDHF J Appl Physiol, December 1, 2001; 91(6): 2561 - 2566. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. S. Scotland, S. Chauhan, P. J.T. Vallance, and A. Ahluwalia An Endothelium-Derived Hyperpolarizing Factor-Like Factor Moderates Myogenic Constriction of Mesenteric Resistance Arteries in the Absence of Endothelial Nitric Oxide Synthase-Derived Nitric Oxide Hypertension, October 1, 2001; 38(4): 833 - 839. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Wu, A. Huang, D. Sun, J. R. Falck, A. Koller, and G. Kaley Gender-specific compensation for the lack of NO in the mediation of flow-induced arteriolar dilation Am J Physiol Heart Circ Physiol, June 1, 2001; 280(6): H2456 - H2461. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Huang, D. Sun, M. A. Carroll, H. Jiang, C. J. Smith, J. A. Connetta, J. R. Falck, E. G. Shesely, A. Koller, and G. Kaley EDHF mediates flow-induced dilation in skeletal muscle arterioles of female eNOS-KO mice Am J Physiol Heart Circ Physiol, June 1, 2001; 280(6): H2462 - H2469. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Lamping Interactions Between NO and cAMP in the Regulation of Vascular Tone Arterioscler Thromb Vasc Biol, May 1, 2001; 21(5): 729 - 730. [Full Text] [PDF]
|
|
|
|
|
|
K. G. Lamping and F. M. Faraci Role of Sex Differences and Effects of Endothelial NO Synthase Deficiency in Responses of Carotid Arteries to Serotonin Arterioscler Thromb Vasc Biol, April 1, 2001; 21(4): 523 - 528. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. W. GRANGE, E. ISOTANI, K. S. LAU, K. E. KAMM, P. L. HUANG, and J. T. STULL Nitric oxide contributes to vascular smooth muscle relaxation in contracting fast-twitch muscles Physiol Genomics, February 7, 2001; 5(1): 35 - 44. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. G. Lamping, D. W. Nuno, E. G. Shesely, N. Maeda, and F. M. Faraci Vasodilator mechanisms in the coronary circulation of endothelial nitric oxide synthase-deficient mice Am J Physiol Heart Circ Physiol, October 1, 2000; 279(4): H1906 - H1912. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. L. Ceiler and J. G. R. De Mey Chronic NG-Nitro-L-Arginine Methyl Ester Treatment Does Not Prevent Flow-Induced Remodeling in Mesenteric Feed Arteries and Arcading Arterioles Arterioscler Thromb Vasc Biol, September 1, 2000; 20(9): 2057 - 2063. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. P. Brandes, F.-H. Schmitz-Winnenthal, M. Feletou, A. Godecke, P. L. Huang, P. M. Vanhoutte, I. Fleming, and R. Busse An endothelium-derived hyperpolarizing factor distinct from NO and prostacyclin is a major endothelium-dependent vasodilator in resistance vessels of wild-type and endothelial NO synthase knockout mice PNAS, August 15, 2000; 97(17): 9747 - 9752. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. G. Geary, D. N. Krause, and S. P. Duckles Estrogen reduces mouse cerebral artery tone through endothelial NOS- and cyclooxygenase-dependent mechanisms Am J Physiol Heart Circ Physiol, August 1, 2000; 279(2): H511 - H519. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||