| First Author | Shields KM | Year | 2011 |
| Journal | Am J Pathol | Volume | 178 |
| Issue | 1 | Pages | 98-109 |
| PubMed ID | 21224048 | Mgi Jnum | J:168238 |
| Mgi Id | MGI:4887496 | Doi | 10.1016/j.ajpath.2010.11.025 |
| Citation | Shields KM, et al. (2011) Mitogen-activated protein kinase phosphatase-1 is a key regulator of hypoxia-induced vascular endothelial growth factor expression and vessel density in lung. Am J Pathol 178(1):98-109 |
| abstractText | 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) ( approximately 5182 m [ approximately 17,000 feet]) for 6 weeks. Hypoxia enhanced phosphorylation of p38 MAP kinase, a substrate of MKP-1, as well as alpha smooth muscle actin (alphaSMA) expression in vessels, respiratory epithelium, and interstitium of phosphatase-deficient lung. alphaSMA-positive vessel (<50 mum 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. |
