Angiotensin-(1-7) Reverses Angiogenic Dysfunction in Corpus Cavernosum by Acting on the Microvasculature and Bone Marrow-Derived Cells in Diabetes

Introduction Angiotensin (Ang)-(1-7) is a recently identified vasoprotective heptapeptide, and it appears to activate the reparative functions of bone marrow-derived stem/progenitor cells (BMPCs). Aim This study evaluated the effect of Ang-(1-7) in the angiogenic function of cavernosum in type 1 diabetes (T1D) and delineated the role of BMPCs in this protective function. Methods T1D was induced by streptozotocin in mice, and mice with 20-24 weeks of diabetes were used for the study. Ang-(1-7) was administered subcutaneously by using osmotic pumps. Cavernosa, and BMPCs from peripheral blood and bone marrow were evaluated in different assay systems. Main Outcome Measures Angiogenic function was determined by endothelial tube formation in matrigel assay. Circulating BMPCs were enumerated by flow cytometry and proliferation was determined by BrdU incorporation. Cell-free supernatant of BMPCs were collected and tested for paracrine angiogenic effect. Expression of angiogenic factors in BMPCs and cavernosa were determined by real-time polymerase chain reaction. Results Ang-(1-7) (100nM) stimulated angiogenesis in mouse cavernosum that was partially inhibited by Mas1 receptor antagonist, A779 (10M) (P<0.05). In cavernosa of T1D, the angiogenic responses to Ang-(1-7) (P<0.005) and VEGF (100nM) (P<0.03) were diminished. Ang-(1-7) treatment for 4 weeks reversed T1D-induced decrease in the VEGF-mediated angiogenesis. Ang-(1-7) treatment increased the circulating number of BMPCs and proliferation that were decreased in T1D (P<0.02). Paracrine angiogenic function of BMPCs was reduced in diabetic BMPCs, which was reversed by Ang-(1-7). In diabetic BMPCs, SDF and angiopoietin-1 were upregulated by Ang-(1-7), and in cavernosum, VEGFR1, Tie-2, and SDF were upregulated and angiopoietin-2 was down-regulated. Conclusions Ang-(1-7) stimulates angiogenic function of cavernosum in diabetes via its stimulating effects on both cavernosal microvasculature and BMPCs. Singh N, Vasam G, Pawar R, and Jarajapu YPR. Angiotensin-(1-7) reverses angiogenic dysfunction in corpus cavernosum by acting on the microvasculature and bone marrow-derived cells in diabetes. J Sex Med 2014;11:2153-2163.