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Originally published In Press as doi:10.1074/jbc.M010690200 on February 22, 2001

J. Biol. Chem., Vol. 276, Issue 19, 15631-15640, May 11, 2001
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Hypoxia-induced Proliferative Response of Vascular Adventitial Fibroblasts Is Dependent on G Protein-mediated Activation of Mitogen-activated Protein Kinases*

Mita DasDagger §, David M. BoucheyDagger , Marla J. MooreDagger , Daniel C. HopkinsDagger , Raphael A. Nemenoff||**, and Kurt R. StenmarkDagger

From the Dagger  Cardiovascular Pulmonary and Developmental Lung Biology Research Labs and the || Department of Renal Medicine, University of Colorado Health Sciences Center, Denver, Colorado 80262

Hypoxia has been shown to act as a proliferative stimulus for adventitial fibroblasts of the pulmonary artery. The signaling pathways involved in this growth response, however, remain unclear. We tested the hypothesis that hypoxia-induced proliferation of fibroblasts would be dependent on distinct (compared with serum) activation and utilization patterns of mitogen-activated protein (MAP) kinases initiated by Galpha i/o proteins. We found that hypoxia stimulated increases in DNA synthesis and growth of quiescent fibroblasts in the absence of exogenous mitogens and also markedly augmented serum-stimulated growth responses. Hypoxia caused a transient activation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), the time course and pattern of which was somewhat similar to that induced by serum but which was of lesser magnitude. On the other hand, hypoxia-induced activation of p38 MAP kinase was biphasic, whereas serum-stimulated activation of p38 MAP kinase was transient, and the magnitude of activation was greater for hypoxia compared with that of serum stimulation. ERK1/2, JNK1, and p38 MAP kinase but not JNK2 were necessary for hypoxia-induced proliferation because PD98059, SB202190, and JNK1 antisense oligonucleotides nearly ablated the growth response. JNK2 appeared to act as a negative modulator of hypoxia-induced growth because JNK2 antisense oligonucleotides led to an increase in DNA synthesis. In serum-stimulated cells, antisense JNK1 oligonucleotides and PD98059 had inhibitory effects on proliferation, whereas SB202190 led to an increase in DNA synthesis. Pertussis toxin, which blocks Galpha i/o-mediated signaling, markedly attenuated hypoxia-induced DNA synthesis and activation of ERK and JNK but not p38 MAP kinase. We conclude that hypoxia itself can act as a growth promoting stimulus for subsets of bovine neonatal adventitial fibroblasts largely through Galpha i/o-mediated activation of a complex network of MAP kinases whose specific contributions to hypoxia-induced proliferation differ from traditional serum-induced growth signals.

* This work was supported in part by Specialized Center of Research Grant HL 56481 and National Institutes of Health Grant HL 14985.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Supported by a postdoctoral fellowship from the American Heart Association, Arizona, Colorado and Wyoming Affiliate, a Giles Filley Research Award from the American Physiological Society, and a research grant from the American Lung Association. To whom correspondence should be addressed: Campus Box B-131, University of Colorado Health Sciences Center, 4200 East Ninth Ave., Denver, CO 80262. E-mail: Mita.Das@uchsc.edu.

Supported by National Institutes of Health Training Grant HL 07171.

** Supported by National Institutes of Health Grants DK 39902, DK 19928, and HL 62924.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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