title: VEGF receptors mediate hypoxic remodeling of adult ovine carotid arteries.
abstract: Recent studies suggest that VEGF contributes to hypoxic remodeling of arterial smooth muscle, although hypoxia produces only transient increases in VEGF that return to normoxic levels despite sustained changes in arterial structure and function. To explore how VEGF might contribute to long-term hypoxic vascular remodeling, this study explores the hypothesis that chronic hypoxia produces sustained increases in smooth muscle VEGF receptor density that mediate long-term vascular effects of hypoxia. Carotid arteries from adult sheep maintained at sea level or altitude (3,820 m) for 110 days were harvested and denuded of endothelium. VEGF levels were similar in chronically hypoxic and normoxic arteries, as determined by immunoblotting. In contrast, VEGF receptor levels were significantly increased by 107% (VEGF-R1) and 156% (VEGF-R2) in hypoxic compared with normoxic arteries. In arteries that were organ cultured 24 h with 3 nM VEGF, VEGF replicated effects of hypoxia on abundances of smooth muscle α actin (SMαA), myosin light chain kinase (MLCK), and MLC20 and the effects of hypoxia on colocalization of MLC20 with SMαA, as measured via confocal microscopy. VEGF did not replicate the effects of chronic hypoxia on colocalization of MLCK with SMαA or MLCK with MLC20, suggesting that VEGF's role in hypoxic remodeling is highly protein specific, particularly for contractile protein organization. VEGF effects in organ culture were inhibited by VEGF receptor blockers vatalinib (240 nM) and dasatinib (6.3 nM). These findings support the hypothesis that long-term upregulation of VEGF receptors help mediate sustained effects of hypoxia on the abundance and colocalization of contractile proteins in arterial smooth muscle.
authors.affiliation: Divisions of Physiology, Pharmacology, and Biochemistry, Center for Perinatal Biology, Loma Linda University School of Medicine, Loma Linda, California.
authors.forename: Olayemi O
authors.initials: OO
authors.lastname: Adeoye
authors.affiliation: Divisions of Physiology, Pharmacology, and Biochemistry, Center for Perinatal Biology, Loma Linda University School of Medicine, Loma Linda, California.
authors.forename: Vincent
authors.initials: V
authors.lastname: Bouthors
authors.affiliation: Divisions of Physiology, Pharmacology, and Biochemistry, Center for Perinatal Biology, Loma Linda University School of Medicine, Loma Linda, California.
authors.forename: Margaret C
authors.initials: MC
authors.lastname: Hubbell
authors.affiliation: Divisions of Physiology, Pharmacology, and Biochemistry, Center for Perinatal Biology, Loma Linda University School of Medicine, Loma Linda, California.
authors.forename: James M
authors.initials: JM
authors.lastname: Williams
authors.affiliation: Divisions of Physiology, Pharmacology, and Biochemistry, Center for Perinatal Biology, Loma Linda University School of Medicine, Loma Linda, California wpearce@llu.edu.
authors.forename: William J
authors.initials: WJ
authors.lastname: Pearce
mesh_terms: D000818:Animals; D002339:Carotid Arteries / Q000187:drug effects / Q000378:metabolism*; D003285:Contractile Proteins / Q000378:metabolism; D000069439:Dasatinib; D000860:Hypoxia / Q000378:metabolism*; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D009219:Myosin-Light-Chain Kinase / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010793:Phthalazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism*; D012756:Sheep; D013844:Thiazoles / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*; D066253:Vascular Remodeling / Q000187:drug effects / Q000502:physiology*
chemical_list: D003285:Contractile Proteins; D010793:Phthalazines; D011725:Pyridines; D011743:Pyrimidines; D013844:Thiazoles; D042461:Vascular Endothelial Growth Factor A; C404768:vatalanib; D040262:Receptors, Vascular Endothelial Growth Factor; D009219:Myosin-Light-Chain Kinase; D000069439:Dasatinib
keywords: chronic hypoxia; confocal colocalization; myosin light chain kinase; regulatory myosin light chain; smooth muscle α-actin