Chronic hypoxia and VEGF differentially modulate abundance and organization of myosin heavy chain isoforms in fetal and adult ovine arteries
Chronic hypoxia and VEGF differentially modulate abundance and organization of myosin heavy chain isoforms in fetal and adult ovine arteries
复制标题
DOI：
10.1152/ajpcell.00408.2011
复制
发表时间：
2012-11-01
影响因子：
5.5
通讯作者：
Pearce, William J.
中科院分区：
文献类型：
--
作者：
Hubbell, Margaret C.;Semotiuk, Andrew J.;Pearce, William J.
Hubbell MC，Semotiuk AJ，Thorpe RB，Adeoye OO，Butler SM，威廉姆斯JM，Khorram O，皮尔斯WJ.慢性缺氧和VEGF差异调节胎儿和成年绵羊动脉肌球蛋白重链亚型的丰度和组织。Am J Physiol Cell Physiol 303：C1090-C1103，2012.首次发表于2012年9月19日; doi：10.1152/ajpcell.00408.2011。慢性缺氧增加血管内皮生长因子（VEGF），从而促进血管生成。本研究探讨了缺氧增加VEGF也通过平滑肌表型转化重塑动脉壁结构和收缩力的假设。妊娠和非妊娠母羊在妊娠的最后110天保持在海平面（常氧）或3，820 m（缺氧）。取足月胎羊和非妊娠成年羊颈总动脉，剥除内皮，进行体外研究。在缺氧胎儿和成人动脉中，拉伸依赖性收缩应力分别为常氧值的32%和77%。在胎儿（+37%）和成人（+119%）动脉中，低血压低收缩性与非肌肉肌球蛋白重链（NM-MHC）丰度增加相关。相反，缺氧减少平滑肌MHC（SM-MHC）丰度的40%，在胎儿动脉，但增加了123%，在成人动脉。缺氧降低了NM-MHC与平滑肌α-肌动蛋白（SM-α A）在胎儿动脉中的共定位，并降低了SM-MHC与SM-α A在成人动脉中的共定位。用生理浓度（3 ng/ml）的VEGF-A（165）进行器官培养，同样可将牵张依赖性应力降低至对照胎儿和成人值的37%和49%。VEGF受体拮抗剂vatalanib消除了VEGF在成人动脉中的作用，但没有消除胎儿动脉中的作用，这表明年龄依赖性VEGF受体信号传导。VEGF复制了胎儿动脉中NM-MHC与SM-α A共定位的缺氧降低和成人动脉中SM-MHC与SM-α A共定位的缺氧降低。这些结果表明，缺氧增加VEGF不仅促进血管生成，但也可能有助于介导缺氧动脉重塑通过年龄依赖性的平滑肌表型和收缩性的变化。
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 (+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 alpha-actin (SM-alpha A) in fetal arteries and decreased colocalization of SM-MHC with SM-alpha A 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-alpha A in fetal arteries and decreases in colocalization of SM-MHC with SM-alpha 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.