Valsartan impairs angiogenesis of mesenchymal stem cells through Akt pathway.
BACKGROUND
Angiotensin II (AngII) reportedly enhances stem cell proliferation, and type 1 angiotensin II receptor (AT1R) antagonists reduce angiogenesis in a rodent hindlimb ischemic model. Whether AT1R antagonists can alter the angiogenic activity of bone-marrow mesenchymal stem cells (BMSCs) is unknown. The purpose of this study is to investigate whether AT1R antagonists can alter the angiogenic activity of BMSCs and explore the potential mechanism for such an action.


METHODS
Mouse BMSCs were isolated and treated with AngII, an AT1R antagonist, and a type 2 angiotensin II receptor (AT2R) antagonist. Angiogenic activity of BMSCs was detected by vascular endothelial growth factor (VEGF) secretion and tube formation of human umbilical vein endothelial cells (HUVECs). BMSCs isolated from enhanced green fluorescent protein (eGFP)-transgenic mice were allografted into ischemic hindlimbs in mice.


RESULTS
The BMSCs constitutively expressed AT1Rs and AT2Rs. AngII treatment significantly increased VEGF secretion by BMSCs. Valsartan (AT1R antagonist) but not PD123319 (AT2R antagonist) treatment attenuated the AngII-induced promotion of VEGF synthesis by BMSCs. The AngII and AngII receptor antagonist control of angiogenic activity of BMSCs were confirmed by tube formation of HUVECs. AngII treatment promoted phosphorylated Ser473 Akt abundance in BMSCs. RNA interference of an isoform of AT1R, valsartan, and wortmannin treatments attenuated AngII-induced Akt phosphorylation. Allograft of BMSCs significantly increased blood flow and VEGF expression in the gastrocnemius muscles of ischemic hindlimbs, which was attenuated after valsartan treatment.


CONCLUSIONS
AT1R antagonists, via AT-1R/PI3K/Akt pathways, impair the AngII-induced promotion of angiogenic activity of mouse BMSCs.
Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
Cheng-I
CI
Cheng
Chang-Chun
CC
Hsiao
Shinn-Chih
SC
Wu
Shao-Yu
SY
Peng
Hon-Kan
HK
Yip
Morgan
M
Fu
Feng-Sheng
FS
Wang
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013777:Tetrazoles / Q000494:pharmacology*; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000068756:Valsartan
D020533:Angiogenesis Inhibitors; D047228:Angiotensin II Type 1 Receptor Blockers; D013777:Tetrazoles; D000068756:Valsartan; D051057:Proto-Oncogene Proteins c-akt; D014633:Valine