Abstract 18969: Estrogen Rescues Severe Pulmonary Hypertension and Increases Survival Through Stimulation of Neoangiogenesis and Suppression of Inflammation
Introduction: Pulmonary hypertension (PH) is a chronic lung disease that leads to right ventricular (RV) failure. Recently we found that estrogen (E2) can rescue severe PH. As E2 has anti-inflammatory activity in a variety of diseases and promotes angiogenesis in different tissues, we investigated whether the stimulation of angiogenesis and suppression of inflammation in the heart and lungs are the key players in E2-induced rescue of PH.
Methods: Male rats were treated with a s.c. dose of monocrotaline (MCT, 60 mg/kg) to induce PH (n=28). At day 21 when PH was established, one group was euthanized (MCT, n=8), 2 other groups received either E2 (0.017 mg/day, n=11) or E2 plus angiogenesis inhibitor TNP-470 (1.2 mg/day, n=3) for 10 days. Saline treated rats were control (CTRL, n=5). All animals were sacrificed at day 31 except for 6 E2 rats that were followed until day 42. Real time PCR, Western Blot and immunohistology were performed. Values were mean±SE. P<0.05 was significant.
Results: E2 fully rescued PH and increased survival (100% until day 42 vs. 42% with MCT until day 31). Interestingly, E2 failed to rescue PH when applied together with TNP. These data strongly support the vital role of angiogenesis in rescue action of E2. VGEF protein both in RV and lungs was reduced significantly ∼ 5 fold in MCT (RV: 0.19±0.01; Lung: 0.18±0.08 normalized to CTRL) and E2 increased VEGF protein significantly ∼10 fold (RV: 2±0.6 and Lung: 2.3±0.5). Capillary density was also quantified in RV sections double labeled with CD31 and wheat germ agglutinin. Reduced capillary density by MCT was restored fully by E2 (0.65±0.1 micro vessels per cell in MCT and 1.56±0.1 in E2, normalized to CTRL). E2 reduced inflammation in both lung and RV as IL-6 transcript upregulation in MCT (∼22 fold in lung, ∼7 folds in RV, normalized to CTRL) was partially reversed by E2. Consistent with transcripts, IL-6 protein was also upregulated in MCT ∼10 fold and was restored with E2. Lung sections stained with the macrophage marker ED1 showed a significant increase in inflammatory cells in MCT. E2 reversed this increase (from 63±5 cells per field in MCT to15±2 in E2, which was similar to 12±2 in CTRL).
Conclusion: E2 rescues severe PH by stimulating both cardiac and pulmonary neoangiogenesis and suppressing inflammatory signalling.
- © 2010 by American Heart Association, Inc.