Cardiovascular Research Advance Access originally published online on June 19, 2008
Cardiovascular Research 2008 80(1):106-113; doi:10.1093/cvr/cvn170
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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
1 Department of Biomedicine, Vascular Biology, Basel, Switzerland
2 Department of Biomedicine, Cell and Gene Therapy, Basel, Switzerland
3 Department of Biomedicine, Cardiology, University Hospital, CH-4031 Basel, Switzerland
4 Division of Internal Medicine, University Hospital, Rämistrasse 100, CH-8091 Zürich, Switzerland
* Corresponding author. Tel: +41 44 255 2400; fax: +41 44 255 4426. E-mail address: edouard.battegay{at}usz.ch
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.
KEYWORDS Angiogenesis; Hypoxia; Kinins; Heart; ACE-inhibition
Time for primary review: 20 days
These authors contributed equally to the manuscript.