© 1996 American Heart Association, Inc.
Articles |
Wall Remodeling During Luminal Expansion of Mesenteric Arterial Collaterals in the Rat
the Departments of Surgery (J.L.U., S.W.F., H.M.B., S.C.M., M.C.D.) and Physiology and Biophysics (J.L.U.), Indiana University Medical Center, Indianapolis.
Correspondence to Joseph L. Unthank, PhD, Department of Surgery, Indiana University Medical Center, 1001 W 10th St, Indianapolis, IN 46202-2879. E-mail joeu@iusurg.iupui.edu.
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Wall remodeling associated with rapid luminal enlargement of collateral mesenteric arteries in rats was investigated 1 and 4 weeks after creation of a collateral pathway by ligating three to four sequential arteries. Paired observations were made of inner diameters of collateral and normal arteries in the same animals. Arterial blood flow was measured at the final observation. Sections of arteries were processed for morphological measurements. After 4 weeks, inner arterial diameter was increased more at the beginning (63±6%) than the end (25±9%) of the collateral pathway. At 1 and 4 weeks, respectively, cross-sectional areas of collateral relative to normal arteries were increased by 46±5% and 59±13% (lumen), 55±8% and 65±14% (media), and 89±18% and 60±31% (intima). The wall expansion during luminal enlargement resulted in a normal medial thickness:luminal radius relationship. At 1 week postligation, wall shear rate remained elevated and endothelial but not smooth muscle hyperplasia had occurred (intimal nuclei: 40±1.7 collateral versus 24±3.0 normal; medial nuclei: 42±6.8 collateral versus 37±2.1 normal). At 4 weeks, wall shear rate in collaterals was similar to normal arteries, and smooth muscle hyperplasia had taken place (medial nuclei: 84±9.4 collateral versus 44±4.7 normal). The data demonstrate that wall expansion associated with rapid luminal enlargement of these collaterals involves hyperplasia of both endothelial and smooth muscle cells; however, smooth muscle proliferation does not occur until after wall shear rate is reduced. The specific cellular adaptations that occur during collateral development may depend on the level of wall shear and shear-dependent modulation of endothelial growth factors.
Key Words: arterial growth • wall remodeling • endothelium • vascular smooth muscle • hyperplasia
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Introduction |
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The luminal enlargement that occurs in arteries forming collateral pathways after arterial occlusion is well documented in both animals1 2 3 4 and humans.5 Using arteriographic techniques that permitted measurements to the nearest 100 µm, Longland1 was able to study the progressive development of individual collaterals after femoral artery obstruction in the rabbit. At 4, 8, 12, and 16 weeks postobstruction, collateral artery diameters were enlarged
25%, 55%, 60%, and 90% at the beginning of the collateral pathway and 25%, 80%, 120%, and 230% at the end of the collateral path. Longland considered this enlargement of the collaterals to result from an increased blood flow velocity.1 Although other mechanisms may be involved in collateral development,6 7 recent reports support the hypothesis that luminal enlargement of arteries results from chronically elevated blood flow and shear stress. Studies by Kamiya and Togawa8 and Zarins et al9 have demonstrated that luminal enlargement occurs in large arteries when blood flow is increased by arteriovenous fistulas. The results of both of these studies8 9 demonstrate that the increase in blood flow initiated an enlargement of the arterial lumen that proceeded for many months until wall shear stress was restored to normal levels. Similar findings have been recently reported for the radial artery of dialysis patients.10 Langille and O'Donnell11 and Tohda et al12 have presented evidence that the long-term regulation of arterial diameter by blood flow is dependent on an intact endothelium. Recent studies using molecular biology and cell culture techniques have provided insight regarding how the endothelium might mediate vascular growth. As reviewed by Resnick and Gimbrone,13 exposure of endothelial cells to increased shear stress upregulates the transcriptional activity of numerous growth factor genes. It has been suggested that shear stress–induced production of growth factors observed in vitro may explain the shear stress–dependent, long-term regulation of arterial diameter.14 A recent study by Sessa et al15 suggests that even transient elevation of shear stress, as occurs during exercise, is adequate to increase the gene expression of endothelial cell nitric oxide (NO) synthase.
Although arterial luminal expansion is well documented during conditions of elevated wall shear stress and studies suggest that the elevated shear stress could alter the production of growth modulators by the endothelium, relatively little information is available describing how wall constituents are altered during the progression of collateral development. Obviously, substantial wall remodeling must occur when collaterals enlarge as much as 200%.1 Remodeling of the arterial wall during flow-induced diameter regulation may involve reorganization of existing wall constituents, with minimum if any changes in tissue content, as well as increases and/or decreases in cellular and matrix material.16 A thinning of the vascular wall appears to occur during collateral development in the heart.17 18 19 For example, from 3 to 16 weeks after placement of an ameroid constrictor on the left circumflex coronary artery in the pig, small intracoronary and extracardiac collateral vessels were characterized by 25% to 60% thinner walls than similar-sized normal vessels.18 Even after 6 months of development, coronary collaterals are characterized by decreased cross-sectional medial area and reduced medial thickness:luminal radius.19 However, the wall of all vessels undergoing collateral development does not become thinner. Four weeks after bilateral common carotid artery ligation, Lehman et al20 observed the collateral basilar arteries to be 24% larger in inner diameter than arteries from sham-operated controls. The cross-sectional medial area of these collaterals was 50% greater than control arteries, and the medial thickness:radius ratio was similar to control arteries. Medial expansion and normal wall thickness were also reported by Zarins et al9 in iliac arteries 6 months after flow was chronically elevated.
Using a model that permits paired comparisons of the same vessels at multiple time points,21 22 23 we have observed mesenteric artery collaterals in the rat to be enlarged 30% within just 1 week after ligation of adjacent arteries.4 This enlargement occurred only at the beginning of the collateral pathway, where wall shear rate was initially increased 175%. Because previous studies have suggested that the greatest luminal enlargement does not occur initially,1 2 3 we undertook this study to determine whether the collaterals in our model continued to enlarge and whether the intimal and medial cross-sectional areas increased, decreased, or remained constant after 1 and 4 weeks of collateral development. The number of endothelial cell nuclei in the intima and vascular smooth muscle cell nuclei in the media, as well as the indices of cell density, were compared between normal and collateral arteries to provide insight into the cellular mechanisms by which changes occur within the wall of these collaterals.
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Materials and Methods |
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All procedures performed in this study were approved by the Indiana University–Purdue University at Indianapolis Institutional Animal Care and Use Committee. The technique for repeated observation of the intestinal vasculature21 22 23 was used. Male Wistar rats (
200 g, Harlan Sprague Dawley, Indianapolis, Ind) were initially anesthetized with sodium pentobarbital (50 mg/kg IM) and administered atropine (0.4 mg/kg IM) to prevent airway congestion. When mobility was lost, each rat's abdominal region was shaved. The rat was then placed on a heating pad to maintain rectal temperature at 37°C. Supplemental anesthesia (pentobarbital, 10 mg/kg) was administered as needed. The abdominal region was wiped with an alcohol pad, a liquid adhesive (Mastisol, Ferndale Laboratories) applied, and an intestinal support chamber4 attached with modified surgical adhesive drape. A midline abdominal incision was made through the skin and linea alba. The terminal ileum was exteriorized into the support chamber for the creation of a collateral-dependent intestinal segment as previously described.4 In brief, a standardized length of small intestine located near the appendix was selected so that the intended collateral-dependent region would contain 45 to 55 first-order arterioles after the ligation of three to four sequential mesenteric arteries. The bowel was covered with prewarmed (37°C) PBS or plastic wrap at all times during the procedure. The bowel segment was maximally dilated by the addition of a dilator cocktail (10-4 mol/L adenosine and 10-5 mol/L sodium nitroprusside) to the suffusion solution, and video images of the mesenteric arteries at the normal, boundary, midzone, and center regions (Fig 1
) were recorded for later diameter measurement (Olympus SZH dissecting microscope, Olympus Corp; Hamamatsu model C2400-50 CCD video camera, Hamamatsu Photonics KK; Sony SVO-9500MD SVHS VCR and Sony Trinitron monitor model PVM-1343MD, Sony Medical Systems; total magnification x50). At locations shown in Fig 1, mesenteric arteries were carefully isolated from adjacent tissues and ligated with 8-0 nylon suture. The isolation and ligation were performed using the dissecting microscope, with extreme care taken to avoid the adjacent vein, lymphatics, and nerve. After the arterial ligations were completed, the bowel was carefully placed back into the peritoneal cavity, and the incision was closed with a running suture (3-0 Dexon, Davis & Geck Inc). The rats were administered antibiotics for 3 days postoperatively (tetracycline, 1.1% in drinking water) and allowed free access to food and water.
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At the final time of observation (1 or 4 weeks later), rats were again anesthetized, then shaved in the abdominal region. A tracheostomy was performed to ensure a patent airway, and the femoral artery was cannulated to verify that the mean arterial pressure was >90 mm Hg when the diameter measurements were made. The intestinal support chamber was attached as above and the collateral-dependent bowel segment located. In the 4-week group, arterial blood flow was measured (0.5 V perivascular ultrasonic flow probes and model 206 flowmeter, Transonics Systems Inc) in the normal and collateral arteries at the boundary region. Arterial diameters were obtained simultaneously with the flow measurements under both resting and maximally dilated conditions. Wall shear rate (WSR) was then calculated by the formula: 
, where Q is blood flow (mL/s) and r is the vessel radius (cm). With the vasculature maximally dilated, videography was repeated as above for the measurement of inner arterial diameters at normal, boundary, midzone, and center regions.
Next, the vessels were prepared for histological evaluation. To preserve the arteries, a cotton suture was placed around a bowel segment containing the collateral-dependent region and adjacent arteries supplying normal tissue. The suffusion solution was replaced with prewarmed 10% neutral buffered formalin containing dilator (10-4 mol/L adenosine and 10-5 mol/L sodium nitroprusside). In this manner, the vessels were fixed at their maximum diameter for the prevailing in vivo arterial pressure. As the arterial pressure began to drop after 5 to 15 minutes, the bowel segment was tied off with the suture, and the rats were killed with an overdose of anesthesia (150 mg/kg). The bowel segment was then excised and placed in 10% formalin overnight. In our experience, this fixation protocol is superior to perfusion fixation in terms of the number of vessels without intimal infolding, and histological details are comparable for the two methods. After overnight fixation, bowel segments were transferred to PBS. Segments of the mesenteric vascular bundle containing the artery, vein, and lymphatic were removed from boundary and normal regions (Fig 1
). Each segment was dehydrated in ethanol, embedded in plastic (JB4, Polysciences), and sectioned (3 µm thick) so that at least 10 µm intervened between sections. Three sections from each segment were stained with methylene blue–basic fuchsin for morphological assessment. All cross-sections were characterized by media of uniform thickness with vascular smooth muscle cells oriented circumferentially.
Video images of the processed arterial cross-sections were acquired and stored by using an image analysis system (Olympus BHMJ microscope with Image-1/AT, Universal Imaging Corporation; total magnification x400). Measurements of the in vivo inner diameters of arteries at 1 week and 4 weeks and of the wall and luminal areas were made with the image analysis system. The luminal areas (AL) were determined by contrast enhancement and gray level thresholding to select only the region inside the endothelium. Preliminary measurements confirmed that this method gave results similar to manual tracing. The luminal perimeters were also determined with the image analysis software. Next, the total area (AT) of the lumen, intima, and media was determined by tracing the well-defined media-adventitia border while the images were enlarged an additional 100% by the analysis system. The combined area of the intima (I; internal elastic lamina plus endothelium) and the lumen (AL+I) was determined by tracing the medial-intimal border. The medial (M) and intimal areas were then calculated: 
The average medial thickness (TM) was also calculated, by assuming circularity of the arterial cross-sections: 
The total number of nuclei in the endothelial layer of the intima and in the media of each section was manually counted via the microscope at x200. The average for each vessel was determined from the measurements on three cross-sections.
Statistical Analysis
All data were entered into a spreadsheet (Microsoft Excel 5.0). Animal averages for normal and collateral arteries were calculated for statistical comparisons. A statistical software package (GB-Stat 5.0 for Windows, Dynamic Microsystems, Inc) was used for all comparisons. Two-way ANOVA with two repeated factors was used for comparisons of in vivo data (diameters, arterial flow, and wall shear rate in Figs 2 and 3 and the Table). For the statistical evaluation of the histological and morphometric data (Figs 5 through 8), two-way ANOVA was performed, with vessel type (collateral or normal) as a repeated factor within animals. When the ANOVA indicated significant differences (P<.05), post hoc comparisons were performed using the Newman-Keuls method to identify differences between groups. More specific information regarding the analysis and sample size is given in the figure legends. All measurements are reported as mean±SEM.
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Sixteen rats were successfully evaluated for this study. Eleven were studied with the complete experimental protocol after 4 weeks of collateral development, and five were used for morphometric studies after 1 week. The average animal weights were 213±9 g when the model was created and 246±6 g and 374±6 g, respectively, at 1 and 4 weeks postligation.
For this study, we used a model in which repeated observations were made of the same vessels in the rat mesentery. We have previously demonstrated that the surgical procedures and handling of the intestine for repeated observation do not alter microvascular growth and development21 23 even in severely diabetic animals.22 In this study, collateral arteries were compared with adjacent arteries within the same animals (Fig 1). Although this procedure has the advantage of permitting paired comparisons within animals, it assumes that the adjacent arteries are indeed normal and unaffected by the experimental protocols. In three acutely studied animals, resting blood flows in normal arteries (Fig 1) were measured before and after the creation of the collateral-dependent region. These arteries did not experience an increase in blood flow after arterial occlusion (0.67±0.10 mL/min before versus 0.65±0.09 mL/min after arterial ligation; paired t test, P=.34) and are considered to be controls for the collateral vessels.
The animal averages of maximally dilated in vivo diameters of normal and collateral arteries before and 4 weeks after arterial ligation are reported in Fig 2. Before ligation, there were no differences in the inner diameter of normal arteries or collateral arteries at center, midzone, or boundary regions. The average diameter of all arteries at this time was 269±6 µm. Paired comparisons were made of the same arteries within the same regions from before ligation to 4 weeks postligation. The postligation diameters of arteries in normal tissue regions were similar to preligation diameters, while the postligation diameters of collateral arteries in all regions were increased (25±9%, center; 47±9%, midzone; and 63±6%, boundary). From the center to the boundary of the collateral pathway, there was a progressive increase in the 4-week postligation diameter (337±24 µm, center; 385±23 µm, midzone; and 437±21 µm, boundary).
Measurements of blood flow and diameters of normal arteries and collaterals at the boundary regions were made under both resting and maximally dilated conditions for the calculation of wall shear rate. Animal averages for these measurements are reported in the Table. Arterial diameters and blood flows increased during topical application of dilators in both normal and collateral vessels. During maximal dilation, the percent increase in arterial blood flow (90±15% versus 78±11%; P=.64) and diameter (20±5% versus 10±1%; P=.08) were similar for normal and collateral arteries, respectively. The wall shear rates calculated from the flow and diameter measurements are reported in Fig 3. The wall shear rate in collaterals was 1720±86 s-1 and 2270±156 s-1 for resting and dilated conditions, respectively, and was similar to the wall shear rate in normal arteries for comparable conditions.
Representative cross-sections of a maximally dilated normal and collateral artery from the same animal are shown in the micrographs of Fig 4. As these micrographs indicate, the plastic embedding and staining procedures allowed us to readily identify the endothelium, internal elastic lamina, and media in the arterial cross-sections and to determine the number of nuclei in the intima and media. In all vessel sections, the internal elastic lamina was distinct and intact.
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The animal averages for cross-sectional areas of the lumen, media, and intima of maximally dilated normal and collateral arteries at the boundary region are reported in Fig 5 for the two groups of rats (1- and 4-week postligation). For normal arteries at 1-week postligation, luminal, medial, and intimal cross-sectional areas averaged, respectively, 54 100±1330, 21 200±604, and 3990±465 µm2. Luminal and medial areas in normal arteries in the 4-week group were significantly greater, probably associated with normal arterial growth as the rats' body weight increased. Fig 5 demonstrates that major differences were observed in these cross-sectional areas between normal and collateral arteries. Relative to normal arteries and after only 1 week of development, the cross-sectional areas in the collaterals had increased 46±5% (lumen), 55±8% (media), and 88±18% (intima). After 4 weeks of collateral development and compared with normal arteries within the same animals, the cross-sectional areas in collaterals were greater by 59±13% (lumen), 65±14% (media), and 60±31% (intima). Comparisons between collaterals after 1 and 4 weeks of development indicated that the cross-sectional areas of both the lumen and media were greater at 4 weeks by 30%; however, the cross-sectional intimal area was 35% smaller at 4 weeks than 1 week.
The medial thickness and medial thickness:luminal radius ratio of maximally dilated normal arteries and collaterals after 1 and 4 weeks of development are presented in Fig 6. In normal arteries, medial thickness averaged 23±1 µm in the 1-week group and had increased to 27±1 µm in the 4-week group, as shown in Fig 6, top. The medial thickness of the collaterals at the boundary region was about 25% greater than the medial thickness of normal arteries after both 1 and 4 weeks of collateral development. Relative to vessels in the 1-week group, the medial thickness of both normal and collateral arteries was 17% greater at 4 weeks postligation. Although differences existed, as noted in medial thickness between vessel type and from 1 to 4 weeks, Fig 6, bottom, illustrates that the ratio of medial thickness to luminal radius is similar for collateral and normal arteries within each group.
During our initial observation of the arterial cross-sections, we were impressed by the obvious difference in the number of intimal nuclei between the normal and collateral arteries. The micrographs in Fig 4 demonstrate that, relative to the normal artery, nuclei in the intima are both more numerous and closer together in the collateral vessel. Fig 7 compares the number of intimal nuclei in collateral and normal arteries in both groups of animals, both in terms of absolute numbers (Fig 7, top) and expressed as the number per unit perimeter length of the cross-section. There were 24±3.0 and 22±1.1 nuclei in the intima of normal arteries of the 1- and 4-week groups, respectively. Relative to normal arteries within the same animals, there were 94±20% and 88±12% more nuclei, respectively, in the intima of collaterals in the 1- and 4-week groups. There were fewer intimal nuclei in collaterals of the 4- than 1-week group (40±1.7 versus 44±2.0; P<.01). Although the perimeter of the luminal cross-section was greater in collateral than normal arteries (991±35 µm versus 820±29 µm, 1 week; 1248±33 µm versus 1001±40 µm, 4 weeks), the number of intimal nuclei per luminal perimeter was greater in collaterals by 62±17% after 1 week and 54±10% after 4 weeks of development, as shown in Fig 7, bottom. The endothelial cell density (intimal nuclei per 100 µm) was lower in both normal and collateral arteries of the 4-week group than in similar vessels of the 1-week group.
The number of nuclei in the media are reported in Fig 8. Fig 8, top, shows that there were 37±2.1 nuclei present in the medial cross-sections of the normal arteries of the 1-week group. A similar number of nuclei were present in the media of collaterals in the same group and normal arteries in the 4-week group. However, there were 84±9 nuclei present in the medial cross-sections of collateral arteries in the 4-week group. Relative to normal arteries within the same animals of the 4-week group, there were 81±19% more nuclei in the collaterals. In Fig 8, bottom, the number of smooth muscle cell nuclei is expressed relative to the cross-sectional medial area. This figure illustrates that the smooth muscle cell density (nuclei per medial area) is similar in normal arteries of the 1- and 4-week groups. Relative to normal arteries within the same animals, smooth muscle cell density is 28±8% lower in collaterals of the 1-week group but similar in collateral arteries of the 4-week group.
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Unlike earlier studies1 2 3 in other organs and species, the most rapid luminal enlargement of collaterals in our model occurs early after arterial occlusion. Inner diameters of collaterals at the boundary region are increased 30% within the first week4 and an additional 35% during the next 3 weeks (Fig 2
). This rapid initial increase in collateral diameter is consistent with our previous measurements of collateral resistance after femoral artery ligation in the rat; ie, the minimum collateral resistance decreased about 50% within the first week of occlusion24 and only an additional 20% over the next 2 months.25
In our model, at both 1 and 4 weeks after arterial ligation, the greatest diameter enlargement occurred at the beginning of the collateral pathway (boundary region, Unthank et al4 and Fig 2), with no enlargement occurring at the end (center region) of the collateral pathway during the first week.4 The site of greatest luminal enlargement at the boundary region corresponds to the location where shear rate is the most elevated.4 At the center region, where shear rate is not initially increased by acute ligation,4 relatively little enlargement occurred. Earlier studies of shear stress–induced enlargement of arterial diameter demonstrated that several months were required for the arterial lumen to enlarge sufficiently to restore shear stress to normal8 9 in large arteries. For this reason, we had not anticipated that wall shear rate would already be restored to normal in the small collaterals of our model at 4 weeks after abrupt arterial occlusion (Fig 3). We did not measure blood flow in the collateral arteries after 1 week of development. However, for maximally dilated conditions we know that the average collateral diameters at the boundary region were 270, 344, and 437 µm, respectively, for initial measurement, 1 week, and 4 weeks after arterial ligation (see Reference 4 and Fig 2). Arterial blood flow in the boundary collaterals during maximal dilation averaged 1.05 and 1.69 mL/min initially4 and at 4 weeks postligation (Table). On the basis of these data, after 1 week the restoration of wall shear rate to the normal levels observed at 4 weeks (Fig 3) would have been >30% complete if blood flow was already increased to 1.69 mL/min and 80% complete if blood flow had not increased above 1.05 mL/min.
Major adaptations occurred within the wall of the collaterals (Figs 4 through 8) during the rapid luminal expansion. The luminal expansion was not associated with a thinning of the wall as reported for coronary collaterals.17 18 19 Rather, in these developing collateral arteries, the cross-sectional medial area increased with the luminal area (Fig 5) to maintain a normal ratio of medial thickness to luminal radius (Fig 6, bottom) for collaterals within each group. A similar increase in medial area to maintain a normal relationship between the medial thickness and radius has been reported by Lehman et al20 for rabbit cerebral collaterals 4 weeks after arterial occlusion. Although we did not measure pressure in the normal arteries or boundary collaterals in this study, we would expect pressure in these collaterals to be similar to or slightly greater than the pressure in normal arteries. This expectation is based on the enlargement of the collateral lumen (Figs 2, 4, and 5), which would decrease vascular resistance and the percent of mean arterial pressure dissipated at this point, our earlier measurements of pressure at the center of the collateral path,4 and preliminary, unpublished measurements of the pressure in boundary collaterals. If pressure in normal arteries and boundary collaterals is similar, then wall tension would be elevated in collaterals by the extent to which the radius of the collaterals was greater than the radius of normal arteries (Law of Laplace). On the basis of the diameter measurements reported in the Table, the morphometric data of Fig 5, and the assumption of equivalent pressures in normal arteries and boundary collaterals, total wall tension would be 20% to 47% greater in collateral than normal arteries during both rest and maximal dilation. Again assuming comparable pressures, the increase in wall thickness (Figs 5 and 6) observed in boundary collaterals at both 1 and 4 weeks would result in levels of wall stress under dilated conditions that would be similar to normal arteries.
Comparison of the numbers of endothelial and smooth muscle nuclei between normal and collateral vessels provides insight regarding the cellular mechanisms involved in the expansion of the collateral wall. Since the sections of normal and collateral arteries were taken from identical vascular locations (comparable arterial branching order) in the same animals, and because the diameters were similar at the initial time of observation (Fig 2), we would not expect the number of vascular smooth muscle and endothelial cell nuclei to be different in collateral compared with normal arteries unless cellular proliferation or regression had occurred. The increased number of smooth muscle nuclei (Fig 8, top) and similar cell densities (Fig 8, bottom) at 4 weeks suggest that smooth muscle hyperplasia contributes to the increased medial area at this time point. Lehman et al20 also reported that the medial expansion observed in rabbit cerebral collaterals 4 weeks after arterial occlusion occurred by smooth muscle hyperplasia. However, at 1 week, the number of smooth muscle cell nuclei was similar for normal and collateral arteries (Fig 8, top), even though the cross-sectional medial area was increased 60% (Fig 5). Thus, the medial hypertrophy observed after 1 week was not the result of cellular hyperplasia and may have involved cellular hypertrophy26 and/or increased matrix production.16
Changes in blood flow and shear forces can have major effects on the endothelium (see review by Langille16 ). Masuda et al27 have reported the effects of chronic flow elevation on the endothelium in canine carotid arteries. Four weeks after construction of an arteriovenous fistula, which increased blood flow and wall shear rate about 3.5-fold initially, endothelial cell density was increased 50% to 84%. Masuda et al27 reported that the endothelial cells of the flow-loaded arteries were radially thickened, closely packed, and circumferentially narrowed, with marked protrusion of the nuclei into the lumen. The average thickness of the endothelial cells was 37% to 67% greater than in the control arteries. The adaptations we observed in the endothelium of our small collateral arteries at the boundary region (Figs 4 and 7) are consistent with these findings by Masuda et al. After both 1 and 4 weeks of collateral development, there were about 90% more endothelial nuclei in collaterals than normal arteries (Fig 7, top), and the distance between endothelial cell nuclei was decreased (Fig 7, bottom), even though the luminal perimeter had increased. In preliminary studies, we have verified with immunohistochemical techniques that all nuclei counted in the intima were from endothelial cells. All intimal cells and nuclei were stained positively by antibody for endothelial cell NO synthase, but monocytes in the lumen were not stained. Preliminary studies in our laboratory using immunohistochemistry for bromodeoxyuridine to detect DNA synthesis demonstrate positive staining of endothelial cells in collaterals within the first week after arterial ligation, providing additional evidence for endothelial hyperplasia in these vessels.
We believe that changes in the shear forces acting on the collateral wall alter the balance between growth promoters and inhibitors produced by the endothelium. Furthermore, we speculate that the rate of luminal enlargement and the specific nature of the cellular adaptations within the collateral wall vary during collateral enlargement. We believe this variation occurs largely as the magnitude of the shear forces changes and levels of specific growth factors in the vascular wall are altered. This speculation is based on previous studies by numerous investigators. First, an intact endothelium11 28 is required for both increases and decreases in arterial diameter that occur as a result of changes in blood flow or shear rate. In addition, Masuda et al27 have shown that changes in endothelial numbers and morphology precede flow-dependent vascular enlargement in large arteries. Resnick and Gimbrone13 have reviewed studies by many investigators which demonstrate that shear forces can alter gene expression for growth factors in endothelial cells. Kohler et al29 have shown that increased shear is associated with the inhibition of smooth muscle hyperplasia in vivo (in vascular grafts with an intact endothelium).
One of the endothelial genes that exhibits a shear-induced increase in transcriptional activity is the gene for NO synthase.13 14 Results from several studies suggest that NO might have a major role in the luminal enlargement and wall expansion of collateral vessels. In cell culture experiments, NO donors inhibit the proliferation of vascular smooth muscle cells from large arteries30 31 and arterioles32 and promote endothelial cell division.33 34 Nerem et al35 observed that NO production in cultured porcine endothelial cells increased as much as 1500% during exposure to shear stress. Ranjan et al14 have demonstrated that the exposure of cultured endothelial cells to shear stress increases constitutive NO synthase mRNA and protein production twofold to threefold. These investigators proposed that the elevation of endothelial NO synthase by increases in blood flow might be involved in the chronic regulation of arterial diameter.14 However, the regulation of vascular cell growth is complex,36 37 and it is unlikely that a single growth factor is responsible for the adaptations we observed. For example, mRNA levels for platelet-derived growth factor (PDGF) A and B chains have been reported to be increased more than 10 times in cultured endothelial cells exposed to increased shear.38 39 PDGF-B is a powerful mitogenic agent for smooth muscle cells, and PDGF-A can promote protein synthesis and cellular hypertrophy.40 41
Currently available data suggest that a normal media:lumen ratio is maintained during collateral development in the mesentery (current study) and brain20 but not in the heart.17 18 19 The basis for such difference is not clear. Possible explanations include the size of the vessels and rate of initial expansion, the exact location of the vessels in the collateral pathway, the magnitude of changes in blood flow and shear stress, and possibly the age of the animal.
The coronary collaterals studied by White et al18 were substantially smaller than collaterals studied in the mesentery (current study) and brain.20 Many factors are involved in the growth regulation of vascular cells,36 37 and differences may exist in the wall remodeling of different-sized vessels.26 Although the coronary collaterals studied by Angus et al19 had inner diameters similar to or larger than the arteries of the current study, neither their original preocclusion diameters nor the extent to which blood flow and shear stress were increased are known. Advantages of the current model include the ability to determine the rate of luminal enlargement from repeated measurements of diameter at specific vascular sites (Figs 1 and 2) and measurement of blood flow and wall shear rate.4
A major difference between the current study and the investigations of coronary collaterals18 19 is the nature of the occlusion. In our study, arterial ligation produced abrupt occlusion, whereas in the coronary studies18 19 the occlusion was produced gradually by ameroid constrictors. Consequently, the elevation of blood flow and wall shear in the coronary vessels may have been more gradual and/or of lower magnitude than in the current study. If shear stress is not increased as rapidly or to the same magnitude, it is likely variations would occur in both the specific growth factors produced and their level of production, potentially resulting in major differences in wall remodeling.
Furthermore, since the collateral pathway extends from normal tissue to the center of the collateral-dependent tissue region, both the nature and magnitude of the stimulus for growth and remodeling could vary along the collateral pathway. For example, in our previous study4 with this model, we observed collateral enlargement at and near the boundary, where blood flow and shear stress were initially elevated 275% and 175%, respectively, but not at the center, where blood flow was not increased. Schaper and colleagues7 17 have proposed that monocytes that adhere to and invade the vascular wall are the primary source for growth factors responsible for coronary collateral luminal enlargement and wall remodeling. Walpola et al42 43 reported increased monocyte adherence and infiltration in arteries subjected to chronically reduced but not elevated blood flow and shear stress. If monocytes had been the primary source of growth factors in our model, we would have expected the greatest increases in collateral diameter to occur at the center region, where wall shear rates were initially normal or reduced.4
Work by Langille et al44 has also demonstrated that different growth responses to changes in blood flow are observed in arteries of juvenile versus mature rabbits. When blood flow in the common carotid artery was chronically reduced by ligation of the external carotid artery, wall composition was altered in the juvenile but not mature rabbits. For this study, we used rats that were initially 10 weeks old, because the deposition of adipose tissue around the vessels in older animals makes it more difficult for us to obtain paired measurement of vessel diameters in vivo. The age of our animals could have influenced the results of our study. Figs 5 and 6 suggest that some growth did occur in the normal arteries during the 3 weeks that intervened between the time the two groups were studied. However, increases in blood flow do produce both luminal enlargement and wall expansion under some conditions in mature animals.8 9 20
In conclusion, although the influence of chronic elevation of blood flow on arterial diameter is well established, only limited information is available regarding the effect of increased blood flow on the composition of the vascular wall. To our knowledge, the effect of different shear rates on the levels of specific growth factors in the collateral wall has not been investigated. Data from the current study indicate that wall expansion and medial thickening can occur even during rapid luminal enlargement. In our model, both endothelial and smooth muscle hyperplasia occur in the developing collaterals, but endothelial cell division precedes smooth muscle cell proliferation. We propose that the specific cellular adaptations at a given point of collateral development are primarily determined by shear-induced alterations in the balance between endothelial growth inhibitors and promoters. However, both the stimulus for growth and remodeling and the nature of remodeling in developing collaterals in other organs or species or under different conditions of shear stress may be far different from those reported in this study. Future studies are needed to clarify the specific stimuli and identify the particular growth factors that mediate the luminal expansion and wall remodeling that occur during various phases of collateral development. Such studies might provide important insight for potential therapies directed toward the improvement of collateral function in patients with arterial insufficiency.
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Acknowledgments |
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This study was supported by National Institutes of Health grant HL 42989 and grant-in-aid 91-642 from the National Center of the American Heart Association.
Received March 29, 1996; accepted August 22, 1996.
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References |
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Conrad MC, Anderson JL, Garrett JB. Chronic collateral growth after femoral artery occlusion in the dog. J Appl Physiol. 1971;31:550-555.
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