Document Detail


Chronic hypoxia and VEGF differentially modulate abundance and organization of myosin heavy chain isoforms in fetal and adult ovine arteries.
MedLine Citation:
PMID:  22992677     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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 (+37%) and adult (+119%) 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 α-actin (SM-αA) in fetal arteries and decreased colocalization of SM-MHC with SM-αA in adult arteries. Organ culture with physiological concentrations (3 ng/ml) of VEGF-A(165) 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-αA in fetal arteries and decreases in colocalization of SM-MHC with SM-αA 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.
Authors:
Margaret C Hubbell; Andrew J Semotiuk; Richard B Thorpe; Olayemi O Adeoye; Stacy M Butler; James M Williams; Omid Khorram; William J Pearce
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-09-19
Journal Detail:
Title:  American journal of physiology. Cell physiology     Volume:  303     ISSN:  1522-1563     ISO Abbreviation:  Am. J. Physiol., Cell Physiol.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-11-19     Completed Date:  2013-01-22     Revised Date:  2013-12-04    
Medline Journal Info:
Nlm Unique ID:  100901225     Medline TA:  Am J Physiol Cell Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  C1090-103     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Anoxia / physiopathology*
Arteries / embryology,  metabolism*
Female
Fetus / blood supply
Myosin Heavy Chains / genetics,  metabolism*
Oxygen / metabolism
Phthalazines / pharmacology
Pregnancy
Protein Kinase Inhibitors / pharmacology
Protein Transport
Pyridines / pharmacology
Receptors, Vascular Endothelial Growth Factor / antagonists & inhibitors
Sheep / embryology*,  physiology*
Vascular Endothelial Growth Factor A / pharmacology*
Grant Support
ID/Acronym/Agency:
P01 HD031226/HD/NICHD NIH HHS; P01-HD-31226/HD/NICHD NIH HHS; R01 HL054120/HL/NHLBI NIH HHS; R01 NS076945/NS/NINDS NIH HHS; R01-HL-54120/HL/NHLBI NIH HHS; R01-HL-64867/HL/NHLBI NIH HHS; R01-NS-076945/NS/NINDS NIH HHS
Chemical
Reg. No./Substance:
0/Phthalazines; 0/Protein Kinase Inhibitors; 0/Pyridines; 0/Vascular Endothelial Growth Factor A; 5DX9U76296/vatalanib; EC 2.7.10.1/Receptors, Vascular Endothelial Growth Factor; EC 3.6.4.1/Myosin Heavy Chains; S88TT14065/Oxygen
Comments/Corrections

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