Abstract 196: Estrogen Treatment of Decompensated Heart Failure Improves Heart Function by Promoting Cardiac Neoangiogenesis and Reducing Fibrosis
Introduction: Decompensated heart failure (DHF) has been shown to be associated with decreased cardiac angiogenesis and increased fibrosis. Estrogen (E2) has been shown to promote angiogenesis in different tissues, but it is not known if E2 can promote angiogenesis in the heart. Recently we found that E2 can restore the function of DHF, therefore we examined whether E2 rescue of DHF is also associated with stimulation of cardiac angiogenesis and decreased fibrosis.
Methods: A transaortic constriction procedure was performed to induce compensated heart hypertrophy (CHH, n=20) which led to DHF (n=25). Once the ejection fraction (EF) reached ∼30%, mice were treated with E2 pellet (0.012mg/pellet, n=16), or E2 plus the angiogenesis inhibitor TNP-470 (TNP, 30 mg/kg i.p., n=4) for 10 days. Real time PCR was performed to quantify the transcripts of angiogenesis markers. Immunocytochemistry and Masson Trichrome staining were used to quantify vessel density and fibrosis. Data were expressed as mean ± SE and p<0.05 was considered significant.
Results: RT-PCR showed that the transcript levels of VEGF and Hif1a were significantly upregulated in CHH (1.83 ± 0.04 for VEGF and 1.71 ± 0.09 for HiF1a; normalized to CTRL) and downregulated ∼10 fold (0.17 ± 0.06 for VEGF and 0.26 ± 0.01 for HiF1a) in DHF vs. CTRL. E2 treatment of DHF (DHF-E2) upregulated VEGF (3.24 ± 0.1) and Hif1a (3.16 ± 0.09) transcripts by 20 and 12-fold, respectively vs. DHF. When E2 was applied together with TNP, EF did not improve (30 ± 3%), supporting the view that cardiac angiogenesis plays a key role in E2 rescue. To directly quantify microvessel density, tissue sections were stained with CD31 and wheat germ agglutinin. The LV capillary density was significantly higher in CHH and reduced in DHF (2.34 ± 0.10 in CHH vs. 0.66 ± 0.07 in DHF; normalized to CTRL). E2 stimulated neoangiogenesis as the capillary density in DHF-E2 was significantly enhanced (2.83 ± 0.14), and TNP prevented this action of E2 (0.53 ± 0.07). E2 was also able to reverse the increased perivascular and interstitial fibrosis in DHH.
Conclusion: Our results show that E2 plays a pivotal role in improving cardiac function of DHF, and that stimulation of angiogenesis along with reduction of fibrosis are two key mechanisms contributing to E2 rescue of heart function.
- © 2010 by American Heart Association, Inc.