Nifedipine-induced vascular endothelial growth factor secretion from coronary smooth muscle cells promotes endothelial tube formation via the kinase insert domain-containing receptor/fetal liver kinase-1/NO pathway.
Endothelial cells (ECs) are the critical cellular element responsible for postnatal angiogenesis. Since the calcium channel blocker (CCB) nifedipine indirectly upregulates endothelial superoxide dismutase expression by stimulating the production of vascular endothelial growth factor (VEGF) from smooth muscle cells (SMCs), we examined whether nifedipine would induce human coronary artery endothelial cell (HCEC) tube formation via an increase in VEGF production from human coronary artery SMCs (HCSMCs) in an in vitro model. Nifedipine stimulated VEGF production from HCSMCs, and this stimulation was abolished by protein kinase C (PKC) inhibitors and a bradykinin B2 receptor antagonist. In addition, supernatant derived from nifedipine-treated HCSMCs induced HCEC tube formation. This tube formation was inhibited by pretreatment with a specific inhibitor of kinase insert domain-containing receptor/fetal liver kinase-1 (KDR/Flk-1) tyrosine kinase and an inhibitor of nitric oxide (NO) synthase. In conclusion, nifedipine increases VEGF secretion through PKC activation via the B2 receptor. The VEGF secretion directly induces HCEC tube formation via the KDR/Flk-1/NO pathway. CCBs may thus have novel beneficial effects in improving coronary microvascular blood flow in addition to their main effect of reducing blood pressure.
Miura
Shin-Ichiro
S
Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan. miuras@cis.fukuoka-u.ac.jp
Fujino
Masahiro
M
Matsuo
Yoshino
Y
Tanigawa
Hiroyuki
H
Saku
Keijiro
K
D065094:Bradykinin B2 Receptor Antagonists; D002478:Cells, Cultured; D003326:Coronary Circulation; D003331:Coronary Vessels / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008833:Microcirculation; D032389:Myocytes, Smooth Muscle / Q000187:drug effects*; D009543:Nifedipine / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000187:drug effects*; D011493:Protein Kinase C / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
D065094:Bradykinin B2 Receptor Antagonists; D042461:Vascular Endothelial Growth Factor A; D019001:Nitric Oxide Synthase; D040301:Vascular Endothelial Growth Factor Receptor-2; D011493:Protein Kinase C; D009543:Nifedipine