Published Online
on March 5, 2007

A more recent version of this article appeared on May 1, 2007

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Submitted on September 18, 2006
Revised on October 11, 2006

Angiotensin II Induces Angiogenesis in the Hypoxic Adult Mouse Heart In Vitro Through an AT₂-B2 Receptor Pathway

Veronica C. Munk; Lourdes Sanchez de Miguel; Marco Petrimpol; Nicole Butz; Andrea Banfi; Urs Eriksson; Lutz Hein; Rok Humar; and Edouard J. Battegay^*

From the Department of Research, Laboratory of Vascular Biology (V.C.M., L.S.d.M., M.P., N.B., R.H., E.J.B.), Medical Outpatient Department (E.J.B.), Department of Research and Department of Surgery, Cell and Gene Therapy (A.B.), and Department of Research, Experimental Critical Care (U.E.), University Hospital, Basel, Switzerland; and Institut für Experimentelle und Klinische Pharmakologie und Toxikologie (L.H.), Freiburg, Germany.

^* To whom correspondence should be addressed. E-mail: ebattegay{at}uhbs.ch.

Abstract--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% O₂) and hypoxia (1% O₂) 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 (AT₁) receptor blockade by losartan did not affect angiotensin II-induced sprouting in wild-type mice. Conversely, the angiotensin II type 2 (AT₂) receptor antagonist PD 123319 blocked this response. In hearts from AT₁^-/- mice, angiotensin II-elicited sprouting was preserved but blocked again by AT₂ receptor antagonism. In contrast, no angiotensin II-induced sprouting was found in preparations from hearts of AT₂^-/- mice. Angiotensin II-mediated angiogenesis was also abolished by a specific inhibitor of the B2 kinin receptor in both wild-type and AT₁^-/- 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 AT₂^-/- 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 AT₂ receptor through a mechanism that involves bradykinin, its B2 receptor, and NO as a downstream effector.

Key words: heart • angiotensin II • bradykinin • losartan • nitric oxide

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