What is the clinical evidence from this study?

Study design: Other. Population: Ischemia. Intervention: Aldosterone vs. Controls (no aldosterone), aldosterone plus spironolactone, or aldosterone plus valsartan. Primary outcome: Neovascularization (angiographic score, capillary number, and foot perfusion) (1.4- to 1.5-fold improvement, p=<0.05).

April 13, 2004Open Access

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

Q: What are the key findings of this study?

Aldosterone treatment improved angiographic score, capillary number, and foot perfusion by 1.4-, 1.5-, and 1.4-fold, respectively, in ischemic mice compared with controls (P<0.05).

Key Result

Aldosterone treatment improved angiographic score, capillary number, and foot perfusion by 1.4-, 1.5-, and 1.4-fold, respectively, in ischemic mice compared with controls (P<0.05).

Structured PICO

Does aldosterone improve ischemia-induced neovascularization in mice with femoral artery ligature?

Population

Mice with ischemia induced by right femoral artery ligature, followed for 21 days.

Intervention

Aldosterone (4.5 microg/day), alone or in combination with spironolactone (20 mg/kg per day), valsartan (20 mg/kg per day), or neutralizing VEGF antibody

Comparator

Untreated controls

Outcome

Neovascularization evaluated by microangiography, capillary density measurement, and laser-Doppler perfusion imaging at 21 dayssurrogate

Aldosterone increases neovascularization in the setting of ischemia through activation of Ang II signaling in a mouse model.

Main Result

Effect estimate: 1.4- to 1.5-fold improvement

p-value: p=<0.05

Abstract

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 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.