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J. Biol. Chem., Vol. 279, Issue 35, 37124-37132, August 27, 2004

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Midkine Is Regulated by Hypoxia and Causes Pulmonary Vascular Remodeling^*

Paul R. Reynolds, Michael L. Mucenski, Timothy D. Le Cras, William C. Nichols, and Jeffrey A. Whitsett¶

From the Divisions of Pulmonary Biology and Human Genetics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229-3039

Midkine (MK) is expressed in a precise temporal-spatial pattern during lung morphogenesis; however, its role in pulmonary homeostasis is unknown. Increased MK staining and mRNA expression were observed in the lungs of hypoxia-susceptible CAST/eiJ mice during hypoxia. MK expression was induced by hypoxia in cell lines in vitro. Because the transcription factor hypoxiainducible factor-1 (HIF-1) modulates cellular responses to hypoxia, we tested whether increased expression of MK in the lung was mediated by HIF-1. HIF-1 enhanced the transcription of MK, acting on HIF-1 regulatory elements located in the MK gene promoter. Site-directed mutagenesis of the 3' HIF response element in the MK promoter blocked the stimulatory effects of HIF-1. To directly assess the role of MK on lung morphogenesis, transgenic mice were generated in which MK was expressed in the respiratory epithelial cells of the developing lung. MK increased muscularization of small pulmonary arteries, increasing -smooth muscle actin and caldesmon staining and the expression of myocardin. MK directly enhanced the expression of myocardin and the smooth muscle-specific genes -smooth muscle actin, calponin, and SM-22 in vascular smooth muscle precursor cells. Expression of MK in the respiratory epithelium is regulated by hypoxia and HIF-1. These data provide a model wherein the respiratory epithelium responds to hypoxia via HIF-1-dependent regulation of MK, enhancing myocardin expression to influence pulmonary vascular gene expression.

Received for publication, May 11, 2004 , and in revised form, June 8, 2004.

^* This work was supported by National Institutes of Health Grants HL38859, HL75770, and HL56387 (Pathobiology of Lung Development) (to J. A. W.), HL72894 (to T. D. L. C.), HL72058 (to W. C. N.), and HD07463 (to P. R. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Cincinnati Children's Hospital Medical Center, Division of Pulmonary Biology, 3333 Burnet Ave., Cincinnati, OH 45229-3039. Tel.: 513-636-4830; Fax: 513-636-7868; E-mail: jeff.whitsett{at}cchmc.org.

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