B2-kinin receptor plays a key role in B1-, angiotensin converting enzyme inhibitor-, and vascular endothelial growth factor-stimulated in vitro angiogenesis in the hypoxic mouse heart

• Published in: Cardiovascular research 2008-10, Vol.80 (1), p.106-113
• Main Authors: Sanchez de Miguel, Lourdes, Neysari, Shiva, Jakob, Sonja, Petrimpol, Marco, Butz, Nicole, Banfi, Andrea, Zaugg, Christian E., Humar, Rok, Battegay, Edouard J.
• Format: Article
• Language: English
• Subjects: ACE-inhibition; Angiogenesis; Angiotensin-Converting Enzyme Inhibitors - pharmacology; Animals; Biological and medical sciences; Bradykinin - physiology; Cardiology. Vascular system; Enalapril - pharmacology; Fibroblast Growth Factors - physiology; Heart; Heart - physiology; Hypoxia; Hypoxia - physiopathology; In Vitro Techniques; Kinins; Medical sciences; Mice; Mice, Inbred C57BL; Neovascularization, Physiologic - drug effects; Nitric Oxide - biosynthesis; Receptor, Bradykinin B1 - agonists; Receptor, Bradykinin B1 - physiology; Receptor, Bradykinin B2 - agonists; Receptor, Bradykinin B2 - physiology; Vascular Endothelial Growth Factor A - physiology
• ISSN: 0008-6363; 1755-3245
• DOI: 10.1093/cvr/cvn170

Aims Angiotensin converting enzyme (ACE) inhibition reduces heart disease and vascular stiffness in hypertension and leads to kinin accumulation. In this study, we analysed the role and importance of two kinin receptor subtypes in angiogenesis during ACE inhibition in an in vitro model of angiogenesis of the mouse heart. Methods and results First, we analysed the angiogenic properties of bradykinin and enalapril on wild-type C57Bl/6 and B2 receptor−/− mouse heart under normoxia (21% O2) and hypoxia (1% O2) in vitro and the contribution of B1 and B2 kinin receptors to this effect. Bradykinin induced dose-dependent endothelial sprout formation in vitro in adult mouse heart only under hypoxia (1.7 fold, n = 6, P < 0.05). The B2 receptor mediated sprouting that was induced by bradykinin and vascular endothelial growth factor (VEGF164; n = 6, P < 0.05), but did not mediate sprouting that was induced by growth factors bFGF or PDGF-BB. Enalapril induced sprouting through both the B1 and B2 kinin receptors, but it required the presence of the B2 receptor in both scenarios and was dependent on BK synthesis. B1-receptor agonists induced sprout formation via the B1 receptor (2.5 fold, n = 6, P < 0.05), but it required the presence of the B2 receptor for them to do so. Both B2-receptor and B1-receptor agonist-induced angiogenesis required nitric oxide biosynthesis. Conclusion The kinin B2 receptor plays a crucial role in angiogenesis that is induced by different vasoactive molecules, namely bradykinin, ACE inhibitors, B1-stimulating kinin metabolites, and VEGF164 in an in vitro model of angiogenesis of mouse heart under hypoxia. Therapeutic treatment of hypertensive patients by using ACE inhibitors may potentially benefit the ischaemic heart through inducing B2-dependent heart neovascularization.