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(Hypertension. 2002;39:830.)
© 2002 American Heart Association, Inc.

Scientific Contributions

Endothelial Nitric Oxide Synthase Lies Downstream From Angiotensin II–Induced Angiogenesis in Ischemic Hindlimb

Radia Tamarat; Jean-Sébastien Silvestre; Nathalie Kubis; Joelle Benessiano; Micheline Duriez; Marc deGasparo; Daniel Henrion; Bernard I. Levy

From INSERM U541, Hôpital Lariboisière, IFR Circulation-Paris 7, Université Paris 7-Denis Diderot (R.T., J-S.S., N.K., J.B., M.D., D.H., B.I.L.), Paris, France; and Novartis Pharma AG (M.d.G.), Basel, Switzerland.

Correspondence to Bernard I. Levy, U541-INSERM, Hôpital Lariboisière, 41 Bd de la Chapelle, 75475 Paris cedex 10, France. E-mail levy@ infobiogen.fr

	Abstract

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We assessed the role of angiotensin (Ang) II in ischemia-induced angiogenesis and analyzed the molecular pathways involved in such an effect. Ischemia was produced by unilateral artery femoral occlusion in control, in valsartan-treated (Ang II receptor type I antagonist, 20 mg/kg per day), in Ang II–treated (5 ng/kg per min), and in Ang II and valsartan–treated rats. After 28 days, angiogenesis was assessed by microangiography and capillary density measurement in hindlimbs. The ischemic/nonischemic leg ratio for angiographic score and capillary number increased by 2.6- and 2-fold, respectively, in Ang II–treated rats compared with controls (P<0.01). This was associated with an increase in vascular endothelial growth factor (VEGF; 1.6-fold) and endothelial NO synthase (eNOS; 1.8-fold) protein content within the ischemic leg, assessed by Western blot. Angiotensin type 1 receptor blockade and administration of VEGF neutralizing antibody (2.5 µg IP, twice a week) in Ang II–treated rats completely prevented such Ang II angiogenic effects. The key role of eNOS was then emphasized by using mice deficient in gene encoding for eNOS. In wild-type mice, Ang II (0.3 mg/kg per min) treatment increased by 1.7- and 1.6-fold the ischemic/nonischemic leg for angiographic score and blood perfusion (assessed by laser Doppler perfusion imaging) ratios, respectively (P<0.01). Conversely, no significant changes were observed in Ang II–treated mice deficient in gene encoding for eNOS. Subhypertensive dose of Ang II enhanced angiogenesis associated with tissue ischemia through angiotensin type 1 receptor activation that involved the VEGF/eNOS-dependent pathway.

Key Words: angiogenesis • ischemia • angiotensin II • receptors, angiotensin • endothelium • nitric oxide

	Introduction

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Angiogenesis is a key process involved in pathologic conditions such as tumor growth or ischemic disease. Hence, understanding the mechanism implied in the angiogenic reaction is of major therapeutic importance. Angiogenesis is the growth of new blood vessels from preexisting ones and is a complex process regulated by numerous factors. Among these factors, angiotensin (Ang) II, the main effector peptide of the renin-angiotensin system, may contribute to vessel growth regulation. Indeed, Ang II stimulates endothelial and smooth muscle cells proliferation in vitro,¹ increases vessel density in rat cremaster muscle² and in the chorioallantoic membrane of the chick embryo,³ and activates in vivo angiogenesis in the rat subcutaneous sponge granuloma.⁴ However, ACE inhibitors have been reported to either block neovascularization in the rat cornea⁵ and microvascular growth in normotensive rats⁶ or increase vessel density in the ischemic hindlimb.⁷ Therefore, the role of Ang II in angiogenesis is still controversial.

Ang II acts by binding to its 2 isoform receptors, angiotensin type 1(AT₁) and type 2 (AT₂). The vast majority of the known vascular and renal actions of Ang II are thought to be mediated via the AT₁ receptor. Ang II–induced activation of endothelial and smooth muscle cells growth was mediated by the AT₁ receptor.¹ Similarly, in the rat subcutaneous sponge granuloma, the Ang II pro-angiogenic response is hampered by a selective AT₁ receptor antagonist.⁴ Nevertheless, the molecular mechanisms implied in the AT₁ receptor activation associated with Ang II angiogenic effect remained to be defined.

Vascular endothelial growth factor (VEGF) is a key growth factor involved in the regulation of the angiogenic process and may represent a putative target for Ang II–induced angiogenesis. Hence, Ang II increases VEGF and VEGF receptor type 2 expression in retinal endothelial cells.⁸ Ang II also induces angiopoietin-2 and VEGF expression in an in vivo corneal assay.⁹ NO is also an important effector mechanism in angiogenesis and may contribute to VEGF-related pathways. The angiogenic response to VEGF was then impaired in mice deficient in endothelial NO synthase (eNOS) gene.¹⁰

The revascularization ameliorates the outcome of ischemic disease. Despite the potential for neoangiogenesis to hamper the consequences of tissue ischemia, only few studies have focused on the causal role for a specific factor in revascularization after tissue ischemia. In addition, there is little information regarding the molecular pathway underlying vascular collateral growth. We therefore hypothesized that Ang II may modulate neovascularization developing in response to tissue ischemia. We also aimed to identify the cellular events involved in Ang II angiogenic effects.

For this purpose, we used 2 animal models. We used a rat model with operatively induced hindlimb ischemia to assess (1) Ang II angiogenic effect within ischemic tissue, (2) the role of AT₁ receptor in such an effect, and (3) the changes in VEGF/eNOS pathways associated with Ang II–induced vessel growth. We next used a mouse model of operatively induced hindlimb ischemia to investigate the impact-targeted disruption of the gene encoding for eNOS on Ang II–induced angiogenesis.

	Methods

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Animal Model: Rat Ischemic Hindlimb Model
This study was conducted in accordance with both institutional guidelines and those formulated by the European community for experimental animal use (L358 to 86/609EEC). Twelve-week-old male normotensive Wistar rats (IFFA-CREDO, Les Arbresles, France) were used for this study. The right femoral artery was occluded (3-0 silk suture) under pentobarbital anesthesia (50 mg/kg IP). The ligature was performed on the femoral artery 0.5 cm proximal to the bifurcation to the saphenous and popliteal arteries, as previously described.¹¹ An osmotic minipump (2 ML4; Alza Corp) was then implanted subcutaneously, allowing the chronic treatment of rats with Ang II, the AT₁ receptor blocker valsartan, or vehicle for 28 days. Rats were randomly assigned to one of the following groups: (1) control group, or vehicle (n= 7); (2) valsartan (20 mg/kg per day, n=5); (3) Ang II (5 ng/kg per min, n=7), 4); Ang II and valsartan (5 ng/kg per min and 20 mg/kg per day, respectively, n=7); and (5) Ang II (5 ng/kg/min) and a-VEGF neutralizing antibody (2.5 µg IP twice a week, R&D systems; n=5).

Animal Model: Mice Ischemic Hindlimb Model
Male C57BL/6J eNOS^-/- mice and eNOS^+/+ mice (Iffa Creddo) underwent surgery to induce unilateral hindlimb ischemia, as previously described.¹¹ Wild-type and eNOS^-/- mice (5 animals per group) were then treated with or without Ang II (0.3 mg/kg per day) using an osmotic minipump (Model 2004, Alza Corp) for 28 days.

Quantification of Angiogenesis
Microangiography
Vessel density was evaluated by high-definition microangiography at the end of the treatment period, as previously described.¹¹ Briefly, animals were anesthetized (isoflurane inhalation), and a contrast medium (barium sulfate, 1 g/mL) was injected through a catheter introduced into the abdominal aorta. Images acquired by a digital X-ray transducer were assembled to obtain a complete view of the hindlimbs (Figure 1). The angiographic score was expressed as a percentage of pixels per image occupied by vessels in the quantification area.

View larger version (100K): [in this window] [in a new window]   Figure 1. Top, Representative microangiography of the right ischemic and left nonischemic hindlimbs, 28 days after femoral artery occlusion in rats. Bottom, Representative photomicrographs of ischemic muscle sections hybridized with antibody directed against total fibronectin. Capillaries appear in white and myocytes in black. Cont indicates control; Ang II, Ang II–treated rats.

Capillary Density
Microangiographic analysis was completed by assessment of capillary density, as previously described.¹¹ Ischemic and nonischemic muscles were dissected and progressively frozen in isopentane solution cooled in liquid nitrogen. Sections (7 µm) were incubated with rabbit polyclonal antibody directed against total fibronectin (dilution, 1:50) to identify capillaries (Figure 1). Capillary density was then calculated in randomly chosen fields of a definite area, using Optilab/Pro software.

Laser-Doppler Perfusion Imaging
To provide functional evidence for ischemia-induced changes in vascularization, laser-Doppler perfusion imaging experiments were performed in mice, as previously described.¹¹ Briefly, excess hairs were removed by depilatory cream from the limb before imaging, and mice were placed on a heating plate at 37°C to minimize temperature variation. Nevertheless, to account for variables, including ambient light and temperature, calculated perfusion was expressed as a ratio of right (ischemic) to left (nonischemic) leg.

Determination of VEGF and eNOS Protein Expression
VEGF and eNOS protein expression were determined by Western blot in ischemic and nonischemic legs, as previously described.¹¹

Statistical Analysis
Results are expressed as mean±SEM. One-way ANOVA was used to compare each parameter. Post hoc Bonferonni’s t test comparisons were then performed to identify which group differences account for the significant overall ANOVA. A value of P<0.05 was considered significant.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Ang II–Induced Angiogenesis Through AT₁-Receptor Activation: Rat Ischemic Hindlimb Model
Quantification of Angiogenesis
Microangiography
Ang II treatment raised by 2.6-fold the ischemic/nonischemic leg ratio compared with that of control (P<0.01). This effect was prevented by AT₁ receptor blockade and by treatment with neutralizing VEGF antibody (P<0.05 versus Ang II–treated rats) (Figures 1 and 2). Conversely, treatment with valsartan alone tended to decrease vessel density compared with that of untreated controls, but this did not reach statistical significance. No significant changes were observed in the nonischemic hindlimb (data not shown).

View larger version (29K): [in this window] [in a new window]   Figure 2. Top, Ischemic/nonischemic vessel density. Bottom, Ischemic/nonischemic capillary density ratio. Values are mean±SEM, n=7 per group. **P<0.01 vs control rats and <P<0.05 vs Ang II–treated animals. Cont indicates control; Val, valsartan-treated rats (AT1 receptor antagonist); Ang II, Ang II–treated rats; Ang II+Val, rats treated with Ang II and valsartan; and Ang II+a-VEGF, rats treated with Ang II and VEGF neutralizing antibody.

Capillary Density
Microangiographic data were confirmed by capillary density analysis. Indeed, Ang II treatment increased by 2-fold the ischemic/nonischemic capillary number ratio compared with that of control (P<0.01). This effect was inhibited by AT₁ receptor blockade and by treatment with neutralizing VEGF antibody (P<0.05 versus Ang II–treated rats) (Figures 1 and 2). Conversely, treatment with valsartan alone tended to decrease capillary density compared with that of untreated controls, but this did not reach statistical significance. No significant changes were observed in the nonischemic hindlimb (data not shown).

Molecular Mechanisms of Ang II–Induced Angiogenesis
Regulation of VEGF Protein Level
In the nonischemic leg, VEGF protein level was unaffected in either group. In contrast, in the ischemic hindlimb, Ang II enhanced VEGF protein content by 65% compared with that of control (P<0.01). Such an effect was hampered by AT₁ receptor blockade (P<0.01 versus Ang II–treated rats) but not by administration of neutralizing VEGF antibody (P=NS versus Ang II–treated rats). Treatment with valsartan alone did not significantly affect VEGF protein content compared with untreated controls (Figure 3).

View larger version (31K): [in this window] [in a new window]   Figure 3. A, Representative Western blot of VEGF protein content in ischemic leg, 28 days after femoral artery occlusion. B, Quantitative evaluation of VEGF protein levels expressed as a percentage of nonischemic control. Values are mean±SEM, n=7 per group. **P<0.01 vs control rats and <P<0.01 vs Ang II treated animals. Abbreviations as in Figure 2.

Regulation of eNOS Protein Level
In the nonischemic leg, eNOS protein level was unaffected in either group. In contrast, in the ischemic hindlimb, Ang II raised by 76% eNOS protein content compared with that of control (P<0.01). Such an effect was hampered by AT₁ receptor blockade and by treatment with neutralizing VEGF antibody (P<0.01 versus Ang II–treated rats). Administration of valsartan alone did not modulate eNOS levels compared with untreated controls (Figure 4).

View larger version (36K): [in this window] [in a new window]   Figure 4. A, Representative Western blot of eNOS protein content in ischemic leg, 28 days after femoral artery occlusion. B, Quantitative evaluation of eNOS protein levels expressed as a percentage of nonischemic control. Values are mean±SEM, n=7 per group. **P<0.01 vs control rats and P<0.01 vs Ang II–treated animals. Abbreviations as in Figure 2.

Role of eNOS in Ang II–Induced Angiogenesis: Mice Ischemic Hindlimb Model
Quantification of Angiogenesis
Microangiography
The ischemic/nonischemic leg ratio was decreased by 2-fold in eNOS^-/- mice compared with eNOS^+/+ mice (P<0.05). Ang II treatment increased by 1.7-fold the ischemic/nonischemic leg ratio in eNOS^+/+ mice (P<0.01 versus untreated eNOS^+/+ mice) but not in eNOS^-/- mice (0.39±0.02 versus 0.42±0.04 in eNOS^-/- mice and Ang II–treated eNOS^-/- mice, respectively, P=NS) (Figure 5).

View larger version (61K): [in this window] [in a new window]   Figure 5. Top, Representative microangiography of the right ischemic and left non-ischemic hindlimbs, 28 days after femoral artery occlusion in mice. Bottom, Ischemic/nonischemic vessel density. Values are mean±SEM, n=5 per group. *P<0.05, **P<0.01 vs eNOS+/+ mice. eNOS+/+ indicates wild-type control; eNOS+/++Ang II, Ang II–treated wild-type control; eNOS-/-, eNOS-deficient mice; and eNOS-/-+Ang II, Ang II-treated eNOS-deficient mice.

Capillary Density
Microangiographic data were confirmed by capillary density analysis. The ischemic/nonischemic leg ratio was decreased by 1.7-fold in eNOS^-/- mice compared with eNOS^+/+ mice (0.38±0.03 versus 0.66±0.02, respectively, P<0.05). Ang II treatment increased by 1.7-fold the ischemic/nonischemic leg ratio in eNOS^+/+ mice (1.12±0.11, P<0.01 versus untreated eNOS^+/+ mice) but not in eNOS^-/- mice (0.38±0.03 versus 0.37±0.05 in eNOS^-/- mice and Ang II–treated eNOS^-/- mice, respectively, P=NS).

Laser-Doppler Perfusion Imaging
Microangiographic and capillary density measurements were associated with changes in blood perfusion. The ischemic/nonischemic leg ratio was reduced by 1.4-fold in eNOS^-/- when compared with eNOS^+/+ mice (P<0.01). Ang II treatment raised by 1.6-fold the ischemic/nonischemic leg ratio in eNOS^+/+ mice (P<0.01 versus untreated eNOS^+/+ mice) but not in eNOS^-/- mice (0.39±0.03 versus 0.32±0.03 in eNOS^-/- mice and Ang II–treated eNOS^-/- mice, respectively, P=NS) (Figure 6).

View larger version (46K): [in this window] [in a new window]   Figure 6. Top, Hindlimb blood flow monitored in vivo by laser-Doppler perfusion imaging in eNOS+/+ and eNOS-/- mice with or without Ang II treatment, 28 days after femoral artery occlusion. In color-coded images, normal perfusion is depicted in red; a marked reduction in blood flow of ischemic hindlimb, in blue. Bottom, Quantitative evaluation of blood flow expressed as a ratio of blood flow in ischemic limb to that of in nonischemic limb. Values are mean±SEM, n=5 per group. *P<0.05, **P<0.01 vs eNOS+/+ mice. Abbreviations as in Figure 5.

Molecular Mechanisms of Ang II–Induced Angiogenesis
Regulation of VEGF Protein Level
In the nonischemic leg, VEGF protein level was unaffected in either group. Interestingly, in the ischemic hindlimb, Ang II enhanced by 75% and 70% VEGF protein in eNOS^+/+ and eNOS^-/- mice, respectively (P<0.01 and P<0.05 versus untreated eNOS^+/+ and eNOS^-/- mice, respectively) (Figure 7).

View larger version (41K): [in this window] [in a new window]   Figure 7. Quantitative evaluation of VEGF (A) and eNOS (B) protein levels expressed as a percentage of non-ischemic control. Values are mean±SEM, n=5 per group. *P<0.05 vs eNOS+/+ mice and P<0.05 vs eNOS-/- mice. Abbreviations as in Figure 5. Nd indicates not detected.

Regulation of eNOS Protein Level
As expected, eNOS protein was not detected in hindlimbs of eNOS^-/- mice. In eNOS^+/+ mice, Ang II raised by 50% eNOS protein content within the ischemic leg (P<0.01 versus untreated eNOS^+/+ mice, respectively) (Figure 7).

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The main results of this study are that Ang II increased ischemia-induced angiogenesis through AT₁ receptor activation that involved a VEGF-dependent pathway. This study also evidenced that eNOS acted downstream VEGF and was an imperative of Ang II–induced angiogenesis.

In ischemic diseases, both hypoxia and inflammation play a major role in the control of new vessel growth.¹² The main mechanism of hypoxia-induced angiogenesis involves the rise in hypoxia-inducible factor-1 protein, resulting in increased expression of VEGF.¹² In control rats, 28 days after ligation, the levels of VEGF and eNOS were similar in ischemic and nonischemic legs, probably because of the end of the angiogenic process. Conversely, the treatment with Ang II was associated with a marked increase in VEGF protein content at day 28. Such an effect was hampered by AT₁ receptor blockade. In addition, Ang II angiogenic effect was prevented by both valsartan and VEGF neutralizing antibody. Thus, pro-angiogenic action of Ang II was mediated by the AT₁ receptor through the sustained activation of VEGF production within the ischemic tissue. In the same view, the renin angiotensin system has been shown to modulate the angiogenic response to electrical stimulation in the rat skeletal muscle through the activation of the VEGF-dependent pathway.¹³ In addition, renin gene transfer in Dahl salt-sensitive rats with low plasma renin activity restored angiogenesis and VEGF expression associated with electrical stimulation.¹⁴

The angiogenic effect of VEGF might be mediated by eNOS activation and subsequently by NO production. Previous studies established a role for NO in endogenous revascularization and in VEGF-induced angiogenesis.^10,15 In the present work, we also evidenced that Ang II angiogenic effect was associated with a rise in eNOS protein content. This increase was hampered by treatment with neutralizing antibody against VEGF, confirming that eNOS acted downstream from VEGF. It is likely that part of the Ang II–induced increase in eNOS protein contents could reflect the increased vessel density and thus the greater number of eNOS-producing cells within the ischemic leg. Nevertheless, angiogenesis in eNOS^-/- mice was not improved by Ang II treatment despite an increase in VEGF protein contents, demonstrating that eNOS is required for Ang II–induced vessel growth and lies downstream from Ang II in the revascularization process after ischemia.

It is noteworthy that blockade of endogenous Ang II–related action using valsartan alone did not significantly modulate the angiogenic process and the eNOS and VEGF protein contents. We can speculate that other stimuli may regulate baseline eNOS and VEGF levels and maintain eNOS and VEGF protein to a physiological level despite the blockade of AT₁ receptor. Subsequently, this basal cellular activation might lead to a basal vessel growth in response to tissue ischemia. Then, the apparent discrepancy between the results obtained by blockade of endogenous Ang II–related action and those observed after exogenous administration of Ang II might reflect that numerous pathways and cell types are involved in the basal angiogenic response to ischemia in vivo. Nevertheless, our results highlight the idea that an increase in tissular or plasma Ang II associated with pathological conditions may affect cellular proliferation and vessel growth.

In addition, these results do not preclude that in vivo, Ang II may activate other cellular events than the ones related to VEGF and NO. In this view, cyclooxygenase-2 is required for Ang II–mediated cellular proliferation in vitro and has been reported to affect the angiogenic process.^16,17 In addition, Ang II may stimulate the production of other growth factors such as bFGF.¹⁸ Interestingly, bFGF has been shown to modulate eNOS level and NO production, leading to endothelial cell differentiation into vascular tubes.¹⁹

In conclusion, this study evidenced for the first time that a subhypertensive dose of Ang II enhanced ischemia-induced angiogenesis in a model of operatively induced hindlimb ischemia. Such an angiogenic effect was mediated by AT₁ receptor and activation of VEGF-related pathways. This study also underscored the crucial role of eNOS in Ang II–induced vessel growth.

	Acknowledgments

 
This work was supported by grants from INSERM and Université Paris VII. R.T. is a recipient of a fellowship from Société Française de Pharmacologie.

Received November 6, 2001; first decision November 30, 2001; accepted December 12, 2001.

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