Aldosterone enhances ischemia-induced neovascularization through angiotensin II-dependent pathway.
BACKGROUND
We analyzed the role of aldosterone in ischemia-induced neovascularization and the involvement of angiotensin II (Ang II) signaling in this effect.


RESULTS
Ischemia was induced by right femoral artery ligature in mice treated or not with aldosterone (4.5 microg/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.
Michel
Frédéric
F
INSERM U541, Hôpital Lariboisière, IFR Circulation-Lariboisière, Université Paris, Paris, France.
Ambroisine
Marie-Lory
ML
Duriez
Micheline
M
Delcayre
Claude
C
Levy
Bernard I
BI
Silvestre
Jean-Sébastien
JS
D000450:Aldosterone / Q000494:pharmacology* / Q000627:therapeutic use; D043925:Angiogenesis Inducing Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D001808:Blood Vessels / Q000187:drug effects; D007511:Ischemia / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic; D012333:RNA, Messenger / Q000378:metabolism; D011859:Radiography; D012039:Regional Blood Flow / Q000187:drug effects; D012084:Renin-Angiotensin System; D015398:Signal Transduction; D012867:Skin / Q000098:blood supply; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D043925:Angiogenesis Inducing Agents; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D000804:Angiotensin II; D000450:Aldosterone