Chronic hypoxia and VEGF differentially modulate abundance and organization of myosin heavy chain isoforms in fetal and adult ovine arteries

Abstract

Hubbell MC, Semotiuk AJ, Thorpe RB, Adeoye OO, Butler SM, Williams JM, Khorram O, Pearce WJ. Chronic hypoxia and VEGF differentially modulate abundance and organization of myosin heavy chain isoforms in fetal and adult ovine arteries. Am J Physiol Cell Physiol 303: C1090 -C1103, 2012. First published September 19, 2012 doi:10.1152/ajpcell.00408.2011.-Chronic hypoxia increases vascular endothelial growth factor (VEGF) and thereby promotes angiogenesis. The present study explores the hypothesis that hypoxic increases in VEGF also remodel artery wall structure and contractility through phenotypic transformation of smooth muscle. Pregnant and nonpregnant ewes were maintained at sea level (normoxia) or 3,820 m (hypoxia) for the final 110 days of gestation. Common carotid arteries harvested from term fetal lambs and nonpregnant adults were denuded of endothelium and studied in vitro. Stretch-dependent contractile stresses were 32 and 77% of normoxic values in hypoxic fetal and adult arteries. Hypoxic hypocontractility was coupled with increased abundance of nonmuscle myosin heavy chain (NM-MHC) in fetal (ϩ37%) and adult (ϩ119%) arteries. Conversely, hypoxia decreased smooth muscle MHC (SM-MHC) abundance by 40% in fetal arteries but increased it 123% in adult arteries. Hypoxia decreased colocalization of NM-MHC with smooth muscle ␣-actin (SM-␣A) in fetal arteries and decreased colocalization of SM-MHC with SM-␣A in adult arteries. Organ culture with physiological concentrations (3 ng/ml) of VEGF-A165 similarly depressed stretch-dependent stresses to 37 and 49% of control fetal and adult values. The VEGF receptor antagonist vatalanib ablated VEGF's effects in adult but not fetal arteries, suggesting age-dependent VEGF receptor signaling. VEGF replicated hypoxic decreases in colocalization of NM-MHC with SM-␣A in fetal arteries and decreases in colocalization of SM-MHC with SM-␣A in adult arteries. These results suggest that hypoxic increases in VEGF not only promote angiogenesis but may also help mediate hypoxic arterial remodeling through age-dependent changes in smooth muscle phenotype and contractility.

Contribution of increased VEGF receptors to hypoxic changes in fetal ovine carotid artery contractile proteins

“…Hypoxic increases in MLC 20 abundance also might result from increases in translation efficiency, but available evidence suggests only inhibition of translation by hypoxia (33). Hypoxic increases in MLC 20 might be explained by phenotypic transformation toward a synthetic phenotype, which is characteristic of hypoxia (21). Such a transformation would increase MLC 20 as a component of increased nonmuscle myosin heavy chain expression, which is induced by chronic hypoxia in fetal carotid arteries (21).…”

“…Hypoxic increases in MLC 20 might be explained by phenotypic transformation toward a synthetic phenotype, which is characteristic of hypoxia (21). Such a transformation would increase MLC 20 as a component of increased nonmuscle myosin heavy chain expression, which is induced by chronic hypoxia in fetal carotid arteries (21). In light of evidence that hypoxia can increase protein degradation (45), this mechanism might also contribute to hypoxic increases in MLC 20 abundance.…”

“…This method of quadrant analysis was adapted from flow-cytometry theory (1, 2) and is described elsewhere (9,21). Sections (5 m) on slides were also double-stained for MLC 20 20) and MLCK-MLC20 colocalization (DyLight 488 for MLC 20 and DyLight 633 for MLCK, conjugated; catalog no.…”

Cytokeratin 8 in venous grafts: A factor of unfavorable long-term prognosis in coronary artery bypass grafting patients

“…), prolonged exposure to growth factors (e.g. VEGF) in the experimental models but also in atherosclerotic lesions [26,27]. This phenotypic modulation is usually accompanied by a loss of contractile function together with progressively impaired expression of cytoskeletal markers of maturity.…”

Vascular Endothelial Growth Factor as a Prognostic Parameter in Subjects with “Plateau Red Face”

“…Expression of the VEGF gene is mainly stimulated by hypoxia through mediation of hypoxia-inducible factors (HIF), and is upregulated in vascular smooth muscle cells and endothelial cells under hypoxic conditions (Hubbell et al, 2012;Adeoye et al, 2013;Pichon et al, 2013). Studies (Walter et al, 2001;Hanaoka et al, 2003;Dorward et al, 2007) have shown that circulating VEGF levels may significantly increase when sea level residents acutely ascend to a high altitude, and overproduction of VEGF in the lung attenuates the development of hypoxic pulmonary hypertension due to the protection of an endothelium-dependent function (Partovian et al, 2000;Louzier et al, 2003;Wu et al, 2013).…”