Abstract P025: Modulatory Effect of Angiotensin II on Endothelial Differentiation and Vasculogenic Capacity of Human MSCs
Human bone marrow-derived mesenchymal stem cell (MSC)-based therapy holds great promise as a new approach for cardiovascular regeneration. In heart failure, there is activation of the renin-angiotensin system and increased formation of angiotensin (Ang) II. We tested the hypothesis that Ang II impairs endothelial differentiation and vasculogenic capacity of human MSCs. MSCs were cultured in endothelial growth media (EGM) and treated with vehicle, 1µM Ang II, or 10µM Ang II for 7 days to assess by real time RT-PCR the expression of two markers of endothelial differentiation, platelet endothelial cell adhesion molecule (PECAM) and von Willebrand factor (vWF). Expression of PECAM and vWF increased similarly in each treatment group at day 7, suggesting endothelial differentiation of MSCs. To assess vasculogenesis, MSCs were cultured in EGM for 7 days and then plated on growth factor reduced Matrigel for 5 hours under the following conditions: vehicle, Ang II (1µM), Ang II + type 1 receptor (AT1R) inhibitor (10µM losartan), or Ang II + type 2 receptor (AT2R) inhibitor (0.1µM PD123177). The vascular index (VI) was determined by multiplying the average number of endothelial tubes formed by the average tube length. MSCs treated for 5 hours with 1µM Ang II exhibited a reduced VI (84.5 ± 2.6% of vehicle treated cells, P<0.05). Treatment with Ang II+AT1R inhibitor increased VI (115 ± 4.9% of vehicle, P<0.05) whereas Ang II+AT2R inhibitor decreased VI (77.1 ± 4.1% of vehicle, P<0.05). Chronic treatment for 7 days in EGM with 1µM or 10µM Ang II also showed decreased VI compared to vehicle (75.4 ± 5.4% and 60.7 ± 2% of vehicle, respectively, P<0.01). These results reveal that both acute and chronic treatment with Ang II produces a negative effect on the vasculogenic potential of endothelial-differentiated human MSCs and suggests opposing effects of AT1R and AT2R on vasculogenesis. In conclusion, we propose that selective modulation of AT1R and AT2R mediated pathways may serve as a promising means for enhancing the regenerative capacity of human MSCs in cardiovascular disease.
- © 2011 by American Heart Association, Inc.