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

• Published in: Hypertension (Dallas, Tex. 1979) Vol. 49; no. 5; pp. 1178 - 1185
• Main Authors: Munk, Veronica C, de Miguel, Lourdes Sanchez, Petrimpol, Marco, Butz, Nicole, Banfi, Andrea, Eriksson, Urs, Hein, Lutz, Humar, Rok, Battegay, Edouard J
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.05.2007; Hagerstown, MD Lippincott
• Subjects: Angiotensin II - administration & dosage; Angiotensin II - pharmacology; Animals; Arterial hypertension. Arterial hypotension; Biological and medical sciences; Blood and lymphatic vessels; Blood vessels and receptors; Cardiology. Vascular system; Clinical manifestations. Epidemiology. Investigative techniques. Etiology; Coronary Vessels - drug effects; Coronary Vessels - physiopathology; Dose-Response Relationship, Drug; Fundamental and applied biological sciences. Psychology; Hypoxia - metabolism; Hypoxia - physiopathology; In Vitro Techniques; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Neovascularization, Physiologic; Nitric Oxide - metabolism; Receptor, Angiotensin, Type 1 - metabolism; Receptor, Angiotensin, Type 2 - deficiency; Receptor, Angiotensin, Type 2 - metabolism; Receptor, Bradykinin B2 - deficiency; Receptor, Bradykinin B2 - metabolism; Vertebrates: cardiovascular system; Suboptimal donor; Tetrazole derivatives; Vasodilator agent; Peptide hormone; Kinin; Cardiovascular disease; Non peptide compound; Vascularization; Angiogenesis; Octapeptide; Ischemia; Bradykinin; Losartan; Angiotensin II; Oxygen; Rodentia; AT1 angiotensin receptor; B2 bradykinin receptor; heart; Vertebrata; Mammalia; Mouse; Biphenyl derivatives; Animal; Nitric oxide; Antihypertensive agent; Hypoxia; Angiotensin antagonist
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/HYPERTENSIONAHA.106.080242

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 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.