title: Mitogen-activated protein kinase phosphatase-1 is a key regulator of hypoxia-induced vascular endothelial growth factor expression and vessel density in lung.
abstract: Although mitogen-activated protein kinase phosphatase-1 (MKP-1) is a key deactivator of MAP kinases, known effectors of lung vessel formation, whether it plays a role in the expression of proangiogenic vascular endothelial growth factor (VEGF) in hypoxic lung is unknown. We therefore hypothesized that MKP-1 is a crucial modulator of hypoxia-stimulated vessel development by regulating lung VEGF levels. Wild-type MKP-1(+/+), heterozygous MKP-1(+/-), and deficient MKP-1(-/-) mice were exposed to sea level (SL), Denver altitude (DA) (1609 m [5280 feet]), and severe high altitude (HYP) (∼5182 m [∼17,000 feet]) for 6 weeks. Hypoxia enhanced phosphorylation of p38 MAP kinase, a substrate of MKP-1, as well as α smooth muscle actin (αSMA) expression in vessels, respiratory epithelium, and interstitium of phosphatase-deficient lung. αSMA-positive vessel (<50 μm outside diameter) densities were markedly reduced, whereas vessel wall thickness was increased in hypoxic MKP-1(-/-) lung. Mouse embryonic fibroblasts (MEFs) of all three genotypes were isolated to pinpoint the mechanism involved in hypoxia-induced vascular abnormalities of MKP-1(-/-) lung. Sustained phosphorylation of p38 MAP kinase was observed in MKP-1-null MEFs in response to hypoxia exposure. Although hypoxia up-regulated VEGF levels in MKP-1(+/+) MEFs eightfold, only a 70% increase in VEGF expression was observed in MKP-1-deficient cells. Therefore, our data strongly suggest that MKP-1 might be the key regulator of vascular densities through the regulation of VEGF levels in hypoxic lung.
authors.affiliation: Department of Pediatrics, University of Colorado Denver, Aurora, Colorado, USA.
authors.forename: Kristin M
authors.initials: KM
authors.lastname: Shields
authors.forename: Evgeniy
authors.initials: E
authors.lastname: Panzhinskiy
authors.forename: Nana
authors.initials: N
authors.lastname: Burns
authors.forename: W Michael
authors.initials: WM
authors.lastname: Zawada
authors.forename: Mita
authors.initials: M
authors.lastname: Das
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics / Q000502:physiology*; D000860:Hypoxia / Q000201:enzymology* / Q000503:physiopathology; D019394:Ki-67 Antigen / Q000378:metabolism; D008168:Lung / Q000098:blood supply* / Q000502:physiology; D051379:Mice; D008817:Mice, Mutant Strains; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D018919:Neovascularization, Physiologic; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C558396:Acta2 protein, mouse; D000199:Actins; D019394:Ki-67 Antigen; D042461:Vascular Endothelial Growth Factor A; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse