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(Circulation. 2004;109:1933-1937.)
© 2004 American Heart Association, Inc.

Brief Rapid Communications

Aldosterone Enhances Ischemia-Induced Neovascularization Through Angiotensin II–Dependent Pathway

Frédéric Michel, BSc; Marie-Lory Ambroisine, BSc; Micheline Duriez, BSc; Claude Delcayre, PhD; Bernard I. Levy, MD; Jean-Sébastien Silvestre, PhD

From INSERM U541 (F.M., M.D., B.I.L., J.S.) and INSERM U572 (M.A., C.D.), Hôpital Lariboisière, IFR Circulation-Lariboisière, Université Paris, Paris, France.

Correspondence to Jean-Sebastien Silvestre, U541-INSERM, Hôpital Lariboisière, 41 Bd de la Chapelle, 75475 Paris Cedex 10, France. E-mail Jean-Sebastien.Silvestre{at}larib.inserm.fr

Received September 3, 2003; de novo received November 25, 2003; revision received February 9, 2004; accepted March 9, 2004.

Background— We analyzed the role of aldosterone in ischemia-induced neovascularization and the involvement of angiotensin II (Ang II) signaling in this effect.

Methods and Results— Ischemia was induced by right femoral artery ligature in mice treated or not with aldosterone (4.5 µg/day), aldosterone plus spironolactone (aldosterone receptor blocker; 20 mg/kg per day), or aldosterone plus valsartan (angiotensin type 1 [AT₁] receptor blocker; 20 mg/kg per day). After 21 days, neovascularization was evaluated by microangiography, capillary density measurement, and laser-Doppler perfusion imaging. Protein level of vascular endothelial growth factor (VEGF) was determined by Western blot analysis in hindlimbs. mRNA levels of renin–angiotensin system components were also assessed by semiquantitative reverse transcription–polymerase chain reaction. Angiographic score, capillary number, and foot perfusion were improved in ischemic/nonischemic leg ratio by 1.4-, 1.5-, and 1.4-fold, respectively, in aldosterone-treated mice compared with controls (P<0.05). Aldosterone proangiogenic effect was associated with 2.3-fold increase in VEGF protein content (P<0.05). Treatments with spironolactone or with neutralizing VEGF antibody hampered the proangiogenic effect of aldosterone (P<0.05 versus aldosterone-treated mice). Interestingly, AT₁ receptor blockade completely abrogated the aldosterone proangiogenic effect, emphasizing the involvement of Ang II–related pathway in aldosterone-induced vessel growth. In this view, angiotensinogen mRNA content was 2.2-fold increased in aldosterone-treated mice in reference to controls (P<0.05), whereas that of renin, angiotensin-converting enzyme, and AT₁ receptor subtype was unaffected. Aldosterone treatment also decreased AT₂ mRNA content by 2-fold (P<0.05 versus controls), suggesting that aldosterone may switch the Ang II pathway toward activation of vessel growth.

Conclusions— This study shows for the first time that aldosterone increases neovascularization in the setting of ischemia through activation of Ang II signaling.

Key Words: aldosterone • neovascularization • ischemia • angiotensin

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