Angiotensin II induces angiogenesis in the hypoxic adult mouse heart in vitro through an AT2-B2 receptor pathway.
Angiotensin II is a vasoactive peptide that may affect vascularization of the ischemic heart via angiogenesis. In this study we aimed at studying the mechanisms underlying the angiogenic effects of angiotensin II under hypoxia in the mouse heart in vitro. Endothelial sprout formation from pieces of mouse hearts was assessed under normoxia (21% O(2)) and hypoxia (1% O(2)) during a 7-day period of in vitro culture. Only under hypoxia did angiotensin II dose-dependently induce endothelial sprout formation, peaking at 10(-7) mol/L of angiotensin II. Angiotensin II type 1 (AT(1)) receptor blockade by losartan did not affect angiotensin II-induced sprouting in wild-type mice. Conversely, the angiotensin II type 2 (AT(2)) receptor antagonist PD 123319 blocked this response. In hearts from AT(1)(-/-) mice, angiotensin II-elicited sprouting was preserved but blocked again by AT(2) receptor antagonism. In contrast, no angiotensin II-induced sprouting was found in preparations from hearts of AT(2)(-/-) mice. Angiotensin II-mediated angiogenesis was also abolished by a specific inhibitor of the B2 kinin receptor in both wild-type and AT(1)(-/-) mice. Furthermore, angiotensin II failed to induce endothelial sprout formation in hearts from B2(-/-) mice. Finally, NO inhibition completely blunted sprouting in hearts from wild-type mice, whereas NO donors could restore sprouting in AT(2)(-/-) and B2(-/-) hearts. This in vitro study suggests the obligatory role of hypoxia in the angiogenic effect of angiotensin II in the mouse heart via the AT(2) receptor through a mechanism that involves bradykinin, its B2 receptor, and NO as a downstream effector.
Munk
Veronica C
VC
Department of Research, Laboratory of Vascular Biology, University Hospital, Basel, Switzerland.
Sanchez de Miguel
Lourdes
L
Petrimpol
Marco
M
Butz
Nicole
N
Banfi
Andrea
A
Eriksson
Urs
U
Hein
Lutz
L
Humar
Rok
R
Battegay
Edouard J
EJ
D000804:Angiotensin II / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D003331:Coronary Vessels / Q000187:drug effects* / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D000860:Hypoxia / Q000378:metabolism / Q000503:physiopathology*; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic; D009569:Nitric Oxide / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D044139:Receptor, Angiotensin, Type 2 / Q000172:deficiency / Q000378:metabolism*; D043782:Receptor, Bradykinin B2 / Q000172:deficiency / Q000378:metabolism*
D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D043782:Receptor, Bradykinin B2; D000804:Angiotensin II; D009569:Nitric Oxide