Mitogenic Effect of Angiotensin II on Rat Carotid Arteries and Type II or III Mesenteric Microvessels but Not Type I Mesenteric Microvessels Is Mediated by Endogenous Basic Fibroblast Growth Factor

From the Department of Pathology (E.J.S., D.M.L., M.A.R., S.M.S.), University of Washington, Seattle; the Department of Pathology (J.W.), Wayne State University, School of Medicine, Detroit, Mich; and the University of Maastricht (the Netherlands) (M.J.A.P.D.).

Correspondence to E.J. Su, Department of Pathology, Box 357335, Seattle WA 98195. E-mail enmingsu{at}u.washington.edu

	Abstract

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Abstract—In this study, anti–basic fibroblast growth factor (anti-bFGF) antibody was used to determine whether the mitogenic effect of angiotensin II in vivo could be blocked by neutralizing bFGF in the vessel wall. Animals, divided into six experimental groups, were given (1) angiotensin II, (2) angiotensin II+anti-bFGF antibody, (3) angiotensin II+normal goat IgG (ngIgG), (4) anti-bFGF antibody, (5) ngIgG, and (6) Ringer's solution. Angiotensin II at 435 ng · kg^-1 · min^-1 was infused into rats continuously for 1 week to induce smooth muscle cell replication, and anti-bFGF antibody or ngIgG was injected intravenously 4 times over the 1-week period at a dose of 60 mg/injection. Bromodeoxyuridine (30 mg/mL) was also continuously infused during the 1-week period. The left carotid artery of all animals was balloon-injured on day 4 of the treatment, and all groups were killed for study on day 7. The results showed that angiotensin II significantly stimulated smooth muscle replication in the balloon-injured carotid artery, intact carotid artery, and three branch levels of the mesenteric vascular tree. Anti-bFGF was able to block the mitogenic effect of angiotensin II in larger vessels but not the smallest (type I) microvessels of the mesenteric arterial tree. This differential response may be attributable to the nature of the lesions in type I vessels versus larger vessels: the type I vascular lesion has a large component of proliferating macrophages, whereas the larger vessels show less injury, few macrophages, and varying levels of smooth muscle replication. Our data suggest that the vessel wall remodeling in the angiotensin II–treated larger vessels involves DNA replication that is dependent on the presence of bFGF.

Key Words: angiotensin II • basic fibroblast growth factor • rat • smooth muscle cell

	Introduction

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Smooth muscle cell replication has been implicated in a number of vascular diseases: atherosclerosis, hypertension, and restenosis. A considerable amount of interest has been focused on the study of mechanisms that control the growth of vascular smooth muscle cells. It has been demonstrated that a variety of humoral or local factors, such as angiotensin II, endothelin, catecholamines, and growth factors, may mediate the growth response of smooth muscle cells.^{1 2 3} For example, in cultured smooth muscle cells, angiotensin II has been shown to increase cell size⁴ and DNA replication.^{5 6} Infusion of angiotensin-converting enzyme inhibitors and AT₁ receptor antagonists prevented neointima formation after balloon catheter denudation,⁷ and administration of angiotensin II increased DNA replication in the vessel wall.^{1 3 8} The other molecule recognized as a major mediator in regulating smooth muscle replication, at least in the rat model, is bFGF. bFGF has a marked effect in stimulating smooth muscle replication after gentle endothelial denudation.⁹ Anti-bFGF antibody almost completely abolished first-wave medial smooth muscle replication¹⁰ and inhibited fibromuscular intimal lesion formation after balloon injury.¹¹ Data from both studies strongly suggest that bFGF has a key role in regulating smooth muscle cell proliferation. Moreover, expression of bFGF was also elevated in smooth muscle cells after angiotensin II treatment in vitro.¹² This implies possible interactions between the two mitogens, angiotensin II and bFGF.

The present study was designed to examine possible interactions of bFGF and angiotensin II in controlling smooth muscle cell replication in both normal and injured carotid artery as well as in the mesenteric arterial tree. Our results confirm and extend earlier findings that bFGF is critical in the first wave of smooth muscle replication after balloon injury. Moreover, we show that angiotensin II stimulates smooth muscle replication in balloon-injured as well as uninjured vessels. Furthermore, we find that anti-bFGF antibody interferes with the mitogenic effect of angiotensin II.

	Materials and Methods

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Preparation of Anti-bFGF and Nonimmune Antibodies
Neutralizing antibody against bFGF and ngIgG were prepared. Plasma from both animals was purified identically by caprylic acid precipitation and sepharose column purification.¹³ Anti-bFGF has been previously characterized, showing its inhibitory effect on 3T3 cell proliferation in vitro by [³H]thymidine incorporation measurement and medial smooth muscle replication in vivo after balloon injury.^{10 14}

Experiment Protocol
Three-month-old male Sprague-Dawley rats (450 g, Zivic Miller, Zelienople, Pa) were used for these studies. All animals were allowed rat chow and water ad libitum. On day 0, animals were anesthetized with ketamine HCl (50 mg/kg), xylazine (5 mg/kg), and acepromazine (1 mg/kg) administered intramuscularly. Pumps (Alza Corp) were surgically implanted subcutaneously in the back of the rats. Two pumps (model 2001) were used for each rat. Animals in the angiotensin II–treated groups received one pump filled with angiotensin II (Sigma Chemical Co) at a dose of 435 ng · kg^-1 · min^-1 in Ringer's. Animals in non-angiotensin II–treated groups received a pump filled with Ringer's. All animals received a second pump filled with BrdU at 30 mg/mL. After surgery, each animal was injected via the tail vein with 1 mL of either anti-bFGF (60 mg/mL), nonimmune goat IgG (60 mg/mL), or Ringer's. Animals recovered in 2 hours from the anesthesia. Blood pressure was measured on days 1, 3, and 5 to demonstrate the elevation of blood pressure due to angiotensin II infusion. Animals were also anesthetized with the same anesthetics on days 2, 4, and 6 for a tail vein injection of 60 mg anti-bFGF antibody, ngIgG, or 1 mL Ringer's, depending on their experimental groups. On day 4, during the same anesthesia as for the intravenous injection, the left common carotid artery was deendothelialized by passage of a 2F Fogarty embolectomy catheter that was inserted into the external carotid artery, passed to the aortic arch, inflated, and withdrawn, with twisting, back to the carotid bifurcation, where deflation was performed. This procedure was performed 3 times to ensure a complete endothelial denudation of common carotid artery. The external carotid was tied off, and blood flow was restored through the internal carotid artery. The Animal Care Committee of the University of Washington approved all procedures.

Three days after the carotid injury, animals were anesthetized as described above. Approximately 3 mL of blood was taken from the inferior vena cava for serum preparation, and animals were euthanized with an intravenous injection of pentobarbital. Three rings (3 mm long) of injured and uninjured carotid arteries were taken from each animal and were either immersion-fixed in 4% paraformaldehyde or methyl Carnoy's fixative or embedded in OCT and frozen. The mesenteric bed including the gut was cut into three pieces. Two were immersed in 4% paraformaldehyde and methyl Carnoy's fixative, respectively. The third piece was dissected out on ice to obtain mesenteric vessels (classified as types I, II, and III; Fig 4) to be embedded in OCT blocks and frozen. Tissues fixed in 4% paraformaldehyde and methyl Carnoy's fixative were routinely processed and embedded in paraffin.

View larger version (21K): [in this window] [in a new window]   Figure 4. Classification of mesenteric arteries: type I, type II, and type III mesenteric microvessels; type IV, first branch from superior mesenteric artery.

Histochemistry and Morphometry
Five-micron-thick paraffin sections of carotid arteries were cut. Three sections, at least 50 µm apart, were stained with anti-BrdU by using a specific monoclonal antibody and standard ABC detection described elsewhere.³ Positively stained cells were visualized with DAB (Sigma), and slides were counterstained with hematoxylin. BrdU-stained cells and total cell numbers (estimated by counting nuclei) were counted per vessel cross section (three sections per rat). Replicative indexes were calculated using the following equation: % positive cells=(number of BrdU-positive nuclei per 3 cross sections/total nuclei per 3 cross sections)x100.

Double Immunostaining of Macrophage Marker and BrdU
Double immunostaining was performed by the method of Goto et al.¹⁵ Briefly, 5-µm-thick paraffin sections of the tissue were first stained using an indirect immunoperoxidase method with the primary antibody (ED1, a monoclonal antibody specific for rat macrophage; Serotec)¹⁶ and then colored brown with DAB used as a substrate. A second BrdU-immunoperoxidase staining was then carried out and colored black by DAB/NiCl (0.32%, Sigma). Sections were lightly counterstained with methyl green.

Mesenteric Artery Dissection and Preparation
A random loop of small intestine was cut out and cleaned under a dissection microscope to retrieve microvessel types I, II, and III as described elsewhere¹⁷ and in Fig 4. A minimum of 4 type III vessels, 3 type II vessels, and 8 to 10 type I vessels from each animal were histologically prepared and examined.

Blood Pressures
Systolic blood pressures were taken as described previously.¹⁷ In brief, individual conscious rats were put into restrainers and trained for 2 consecutive days. Then, systolic blood pressures were measured by tail-cuff plethysmography (Narco Biosystems). Three measurements per animal were taken to get a mean value for the day. Blood pressures were measured 2 days before the treatment for baseline value and on days 1, 3, and 5 after angiotensin II pumps were implanted.

Assessment of Tissue Antibody Penetration
Access and penetration of antibodies into vascular tissues was assessed by immunocytochemistry. The presence of goat IgG was detected in carotid cross sections using the Vector ABC ELITE kit for goat according to the manufacturer's instructions. For both anti-bFGF antibody and ngIgG-treated rats, staining was observed in intimal, medial, and adventitial regions of the vessel, indicating equivalent penetration and deposition of both IgGs at the injury sites (data not shown).

Statistics
Values are given as mean±SEM. ANOVA was performed. Comparisons of two group means were made with subsequent Fisher's protected least squares method. A value of P<.05 was considered significant.

	Results

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Angiotensin II Regulation of Blood Pressure
Angiotensin II treatment raised blood pressure significantly (Fig 1). Blood pressure started to rise after 1 day of angiotensin II infusion and reached a peak around day 5 of the treatment. Neither anti-bFGF nor ngIgG treatment had any effect on the blood pressure.

View larger version (11K): [in this window] [in a new window]   Figure 1. Graph showing blood pressure measurement (mean±SEM) in rats receiving continuous subcutaneous infusion of angiotensin II (A-II, 435 ng · kg-1 · min-1) or Ringer's for 1 week beginning on day 0. Antibody against bFGF (anti-bFGF) and ngIgG were given through four intravenously injections on days 0, 2, 4, and 6 (60 mg/injection).

Angiotensin II–Stimulated DNA Replication in the Injured Carotid Artery
Fig 2 shows that infusion of angiotensin II stimulated medial smooth muscle cell replication in the injured carotid artery above the level of replication seen after balloon injury alone. Three days after balloon injury, cumulative BrdU labeling of the injured carotid media was 41.0% with angiotensin II treatment, whereas the Ringer's group showed a 21.5% labeling. The replicative effects of angiotensin II were attenuated by injections of anti-bFGF. Angiotensin II and anti-bFGF together produced a BrdU labeling index of 20.5%, which was significantly lower than that of angiotensin II treatment alone (P<.01). Infusion of ngIgG at the same dose as anti-bFGF did not change the proliferative effects of angiotensin II.

View larger version (11K): [in this window] [in a new window]   Figure 2. Bar graph showing DNA labeling by BrdU staining in the left carotid artery 3 days after balloon injury. Control rats were infused with Ringer's vehicle. Angiotensin II (A-II) was infused at 435 ng · kg-1 · min-1. Antibody against bFGF (anti-bFGF) and ngIgG were given intravenously on days 0, 2, 4 and 6 (60 mg/injection). All rats also received continuous infusions of BrdU for 1 week via a separate pump to label replicating cells. Values are mean±SEM of the labeling index of smooth muscle cells in the arterial wall. *P<.01; **P<.05.

Anti-bFGF by itself significantly attenuated smooth muscle cell replication after balloon injury from 21.5% to 12.9% (P<.05), whereas the ngIgG treatment resulted in a 23.7% BrdU labeling index, which was not different from the Ringer's-only group.

Angiotensin II–Stimulated DNA Replication in the Intact Carotid Artery
One week of angiotensin II infusion stimulated the BrdU labeling index in the media of the uninjured carotid artery from 0.3% (Ringer's group) to 3.5% (Fig 3). This stimulatory effect was significantly inhibited by the infusion of anti-bFGF antibody, which lowered the BrdU index to 2.0% (P<.05). The BrdU labeling index of ngIgG (plus angiotensin II)–treated animals was not different from that of angiotensin II–treated animals.

View larger version (12K): [in this window] [in a new window]   Figure 3. Bar graph showing the replication index of smooth muscle cells in the uninjured carotid artery in the same experiment as described in Fig 2. A-II indicates angiotensin II. Values are mean±SEM of the labeling index of smooth muscle cells in the arterial wall. *P<.01; **P<.05.

Angiotensin II–Stimulated DNA Replication in Type I Mesenteric Microvessels
We examined three major branches in the mesenteric vascular tree. The radial vessels, usually two branch levels from the superior mesenteric artery, are classified as type III. Type II vessels run parallel to the gut, and type I vessels are the smallest, penetrating the gut (Fig 4).

Angiotensin II treatment induced an extraordinarily high replication rate as well as vessel wall remodeling in the type I vessels of the mesentery. Using a double-immunostaining technique, we were able to count the proliferating macrophage, and the results are summarized in Fig 5. Macrophages, identified as ED1-positive cells, had a labeling index of 48.1% in the angiotensin II–treated group. Anti-bFGF treatment did not inhibit this replication process (50.1%). For non-ED1–positive cells, presumably mostly smooth muscle cells, infusion of angiotensin II produced a 50.6% replication index. Anti-bFGF treatment did not abolish this proliferative effect (64.0%). The Ringer's group showed minimal smooth muscle replication with no macrophage present.

View larger version (12K): [in this window] [in a new window]   Figure 5. Bar graph showing cumulative labeling of DNA replication in the type I microvessels. Rats were infused with angiotensin II (A-II, 435 ng · kg-1 · min-1) or Ringer's vehicle for 1 week. Antibody against bFGF (anti-bFGF) and ngIgG were given intravenously on days 0, 2, 4, and 6 (60 mg/injection). BrdU and ED1 were double-immunostained on the same slide to generate individual replication indexes for both macrophage and non-ED1–positive cells. Values are represented as mean±SEM. *P<.01; ns, not significant.

Angiotensin II–Stimulated DNA Replication in Type II and III Mesenteric Microvessels
Infusion of angiotensin II also induced significantly higher replication in smooth muscle cells of type II mesenteric vessels compared with the control Ringer's group. Angiotensin II–treated type II vessels averaged a 38.5% replication index, with the Ringer's group showing only 1.2% (Fig 6A). Anti-FGF antibody significantly reduced the mitogenic effect to a 24.9% proliferative index. ngIgG treatment did not attenuate the mitogenic effect of angiotensin II (35.4%).

View larger version (15K): [in this window] [in a new window]   Figure 6. Bar graph showing cumulative labeling of DNA replication in the type II and type III mesenteric microvessels. Rats were infused with angiotensin II (A-II, 435 ng · kg-1 · min-1) or Ringer's vehicle for 1 week. Antibody against bFGF (anti-bFGF) and ngIgG were given intravenously on days 0, 2, 4, and 6 (60 mg/injection). A, Type II microvessels. B, Type III microvessels. Values are represented as mean±SEM. *P<.01; **P<.05.

The type III vessels showed a similar pattern of proliferative response to angiotensin II. Angiotensin II treatment gave a 40.3% BrdU labeling index over 1 week (Fig 6B). Anti-bFGF reduced this value to 24.2%. ngIgG treatment did not change the mitogenic response of angiotensin II in the type III vessel (37.8%). The Ringer's group had a minimal (2.3%) labeling.

	Discussion

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In the present study, we found that angiotensin II stimulated smooth muscle replication in several different arteries and enhanced the mitogenic responses due to balloon injury. Anti-bFGF treatment inhibited, at least partially, the mitogenic effects of angiotensin II in the carotid arteries and type II or III mesenteric microvessels, but not type I mesenteric microvessels. We also reconfirmed earlier findings that anti-bFGF antibody reduced smooth muscle cell replication in the first wave after balloon injury.¹⁰ This reconfirmation helps to establish the validity of the antibody used in the present study.

These results suggest that angiotensin II may interact with bFGF in the vascular system and elicit its mitogenic effect via bFGF in vivo. A number of studies have already shown that angiotensin II can regulate the expression of bFGF in vitro.^{12 18 19} Itoh et al¹² have demonstrated that angiotensin II induces bFGF synthesis in vascular smooth muscle cells and that this process is blocked by treating the cells with antisense complementary to bFGF. Moreover, this finding was also shown by Koibuchi et al¹⁹ and Ali et al.¹⁸ These data from in vitro studies begin to establish a possible interaction between angiotensin II and bFGF. Our results have extended the findings from in vitro to in vivo, demonstrating that the mitogenic effect of angiotensin II on smooth muscle cells may be mediated via bFGF.

The ability of anti-bFGF to inhibit the mitogenic response of angiotensin II raises several possibilities. First, how does bFGF become available? The mechanism for bFGF release is not well understood because the translational products of bFGF mRNA lack a signal sequence and bFGF cannot be released via the normal secretory pathway.^{20 21} It has been shown, however, that bFGF can be released when cells are mechanically injured.^{22 23} The relevance of these data to physiological responses is debatable. Perhaps most relevant to our data, Kaye et al²⁴ showed that increased myocardial activity induced in vitro by electrical stimuli resulted in a release of bFGF. They attributed this release to increased membrane permeability measured by the uptake of dextran in paced cardiac myocytes. The possibility of a similar vascular injury in response to angiotensin II treatment is supported by several pieces of evidence showing that infusion of angiotensin II causes increased permeability of the vessel wall in the rat mesentery, as demonstrated by increased deposition of carbon particles and morphological evidence of cell death.^{25 26 27} So it is conceivable that bFGF may be released via cell injury due to angiotensin II treatment.

Second, angiotensin II may induce export of bFGF through a nonconventional pathway without compromising the integrity of the cells. Maciag, Jackson, and colleagues^{28 29} have described that acidic FGF, whose structure also lacks a signal sequence for secretion, can be secreted into the conditioned medium after heat shock treatment. This secretion process is inhibited by actinomycin D and cycloheximide treatment. In another study, Florkiewicz et al³⁰ have demonstrated the existence of an alternative, energy-dependent, and nonendoplasmic reticulum/Golgi pathway for bFGF release.

Third, none of our data require that new bFGF be released from cells in response to angiotensin II treatment. The mitogenic effects of angiotensin II could depend on bFGF that is already present in the extracellular matrix. Several groups have described the presence of bFGF in the extracellular matrix of cultured cells.^{31 32} Although similar data are lacking in vivo, the amount of bFGF required to exert an effect, especially if matrix bound, is difficult to determine. It has been suggested that matrix binding of bFGF may provide a reservoir of growth factor.³³ The localization may depend on the strong interaction of bFGF with heparan sulfate proteoglycan in the vessel wall.^{34 35 36} Therefore, it is possible that angiotensin II could play a role in mobilization of the matrix-bound bFGF, thus inducing smooth muscle proliferation, or that the mitogenic effect of angiotensin II could depend on the additive but nonmitogenic activity of the nascent bFGF.

Treatment with anti-bFGF only partially inhibited the mitogenic effect of angiotensin II. This could be due to the dose of antibody or to bFGF-independent pathways present in the vessel wall, including mitogenic and/or antimitogenic factors, such as catecholamines,^{3 37} endothelin,^{38 39} and nitric oxide.^{40 41} For example, we found that prazosin (an ₁-adrenergic antagonist) blunts the proliferative effect of angiotensin II in both injured carotid and intact carotid arteries.³ Phenylephrine (an -adrenergic agonist), on the other hand, can induce smooth muscle replication³⁷ in the carotid artery. These data suggest that catecholamines have mitogenic effects acting, perhaps, downstream from angiotensin II. The relationship of -adrenergic agonists and antagonists to bFGF is, however, unknown.

It is important to note that the proliferation in the smallest mesenteric vessels, the type I arteries penetrating the gut, is not bFGF dependent. Moreover, in angiotensin-infused animals, the morphological pattern of the type I arteries is very different from that seen in the type II and type III mesenteric vessels and in the large carotid arteries. The type I vessels undergo dramatic morphological changes, including fibrinoid necrosis, macrophage infiltration,¹⁷ and macrophage proliferation. Since we used continuous BrdU labeling, we cannot rule out the possibility that the labeled macrophage may come directly from the bone marrow. Possible candidate molecules responsible, at least in part, for local macrophage proliferation in the vessels include GM-CSF and M-CSF.⁴² The macrophage subpopulation in atherosclerotic lesions is associated with the cell proliferation marker.^{43 44} In addition, GM-CSF and M-CSF are predominantly found in macrophage within the plaque.⁴² However, this is not the only example of macrophage replication seen outside of bone marrow. Local macrophage proliferation can also be found in a number of other disease models such as rat antiglomerular basement membrane glomerulonephritis⁴⁵ and rat experimental pancreatitis.¹⁵ The biological significance of the macrophage proliferation is unclear.

Although it is not surprising that anti-bFGF did not block macrophage replication, anti-bFGF also failed to block replication of smooth muscle cells in the type I vessels. Perhaps the smooth muscle cells in the type I vessel respond to a distinct set of growth factors and chemoattractants that are produced by macrophage cells.^{46 47} These factors may override the inhibitory effect of anti-bFGF antibody, thus allowing no reduction of replication of smooth muscle cells in the vessel wall.

The fact that anti-bFGF treatment did not reduce blood pressure suggests that this anti-proliferative effect of anti-bFGF is unlikely to be working through the regulation of blood pressure. Since all animals that received angiotensin II for 1 week became hypertensive, it is not clear whether the elevated level of smooth muscle replication is due at least in part to the effects of hypertension or to the direct action of angiotensin II. Griffin et al⁴⁸ have presented evidence that angiotensin II stimulated microvessel hypertrophy through a nonpressor effect. They showed that treatment using angiotensin II along with hydralazine prevented the rise of pressure and cardiac hypertrophy but failed to abolish the increase of cross-sectional area in type III microvessels.⁴⁸ These data argue for a possible direct hypertrophic action of angiotensin II on the type III microvessels.

In summary, we can begin to consider the pathways that are controlling smooth muscle cell replication in response to angiotensin II. It is possible that angiotensin II may induce smooth muscle cell injury or membrane leakage, thus causing the release of bFGF. If this is true, local access to bFGF may be the final common pathway allowing angiotensin II to act as a mitogen in the vessel wall.

	Selected Abbreviations and Acronyms

 

bFGF = basic fibroblast growth factor BrdU = bromodeoxyuridine DAB = 3,3'-diaminobenzidene GM-CSF = granulocyte-macrophage colony–stimulating factor M-CSF = macrophage colony–stimulating factor ngIgG = nonimmunized goat IgG OCT = ornithine carbamyl transferase Ringer's = Ringer's lactate

	Acknowledgments

 
This study was supported by National Institutes of Health grants HL-07312 and DK-47659. The authors wish to acknowledge the expert assistance of Patti Polinsky and Ben Rampp.

Received April 18, 1997; accepted November 25, 1997.

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