Hypoxia-induced Proliferative Response of Vascular Adventitial Fibroblasts Is Dependent on G Protein-mediated Activation of Mitogen-activated Protein Kinases

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 Gαi/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 Gαi/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 Gαi/o-mediated activation of a complex network of MAP kinases whose specific contributions to hypoxia-induced proliferation differ from traditional serum-induced growth signals. 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 Gαi/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 Gαi/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 Gαi/o-mediated activation of a complex network of MAP kinases whose specific contributions to hypoxia-induced proliferation differ from traditional serum-induced growth signals. pulmonary artery mitogen-activated protein extracellular signal-regulated kinase c-Jun N-terminal kinase Eagle's minimum essential medium fetal bovine serum Change in the architecture of the blood vessel wall occurs in response to a wide range of physiologic stimuli and various injurious insults. In response to chronic hypoxic exposure, the pulmonary arteries (PA)1 undergo concentric thickening with medial and adventitial changes predominating (1Stenmark K.R. Mecham R.P. Annu. Rev. Physiol. 1997; 59: 89-144Crossref PubMed Scopus (294) Google Scholar, 2Stenmark K.R. Fasules J. Voelkel N.F. Henson J. Tucker A. Wilson H. Reeves J.T. J. Appl. Physiol. 1987; 62: 821-830Crossref PubMed Scopus (164) Google Scholar). When the hypoxic exposure occurs in early neonatal life, the adventitial changes are particularly striking and include early and dramatic increases in fibroblast proliferation (1Stenmark K.R. Mecham R.P. Annu. Rev. Physiol. 1997; 59: 89-144Crossref PubMed Scopus (294) Google Scholar, 3Haworth S.G. Eur. Respir. J. 1993; 6: 1037-1043PubMed Google Scholar, 4Morin F.C. Stenmark K.R. Am. J. Respir. Crit. Care Med. 1995; 151: 2010-2032Crossref PubMed Scopus (103) Google Scholar). Much of the work done to date in defining this process has focused on the growth factors that are produced under hypoxic conditions and their potential effects on cell proliferation. Little work, however, has been done on the growth promoting signaling pathways that might be induced by hypoxia itself and thus might affect vascular wall cell proliferation directly and/or markedly influence the response to locally produced growth factors. A better knowledge of this process is important for an understanding of the remodeling process in many vascular diseases because hypoxemic or ischemic conditions are thought to contribute to this process. Mitogen-activated protein (MAP) kinase family members including extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 MAP kinase have been proposed to be important signaling components linking extracellular stimuli to cellular responses including cellular growth, differentiation, and metabolic regulation (5Davis R.J. J. Biol. Chem. 1993; 268: 14553-14556Abstract Full Text PDF PubMed Google Scholar, 6Cobb M.H. Goldsmith E.J. J. Biol. Chem. 1995; 270: 14843-14846Abstract Full Text Full Text PDF PubMed Scopus (1662) Google Scholar, 7Kyriakis J.M. Avruch J. J. Biol. Chem. 1996; 271: 24313-24316Abstract Full Text Full Text PDF PubMed Scopus (1025) Google Scholar, 8Minden A. Karin M. Biochim Biophys. Acta. 1997; 1333: F85-F104PubMed Google Scholar). Mitogen-activated protein kinases can be activated by various external stimuli such as growth factors, hormones acting via G protein-coupled receptors, and physical stresses (6Cobb M.H. Goldsmith E.J. J. Biol. Chem. 1995; 270: 14843-14846Abstract Full Text Full Text PDF PubMed Scopus (1662) Google Scholar, 9Karin M. Curr. Opin. Cell Biol. 1994; 6: 415-424Crossref PubMed Scopus (359) Google Scholar). Hypoxia has also been shown to stimulate ERK, JNK, and p38 MAP kinase in different cell types (10Seko Y. Tobe K. Ueki K. Kadowaki T. Tazaki Y. Circ. Res. 1996; 78: 82-90Crossref PubMed Scopus (112) Google Scholar, 11Seko Y. Takahashi N. Tobe K. Kadowaki T. Yazaki Y. Biochim. Biophys. Acta. 1997; 239: 840-844Google Scholar, 12Scott P.H. Paul A. Belham C.M. Peacock A.J. Wadsworth R.M. Gould G.W. Welsh D. Plevin R. Am. J. Respir. Crit Care Med. 1998; 158: 958-962Crossref PubMed Scopus (47) Google Scholar, 13Laderoute K.R. Mendonca H.L. Calaoagan J.M. Knapp A.M. Giaccia A.J. Strok P.J.S. J. Biol. Chem. 1999; 274: 12890-12897Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar, 14Sodhi C.P. Batlle D. Sahai A. Kidney Int. 2000; 58: 691-700Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, 15Matsuda N. Morita N. Matsuda K. Watanabe M. Biochim. Biophys. Res. Commun. 1998; 249: 350-354Crossref PubMed Scopus (165) Google Scholar). Recently, Jin et N. N. Am. J. Respir. Cell Biol. 2000; PubMed Scopus Google the activation of MAP kinases in pulmonary wall of in response to this not the activation patterns in specific cell types in the vessel of p38 MAP kinase has been to be necessary for the proliferation of bovine adventitial fibroblasts and in response to hypoxia P.H. Paul A. Belham C.M. Peacock A.J. Wadsworth R.M. Gould G.W. Welsh D. Plevin R. Am. J. Respir. Crit Care Med. 1998; 158: 958-962Crossref PubMed Scopus (47) Google Scholar, 14Sodhi C.P. Batlle D. Sahai A. Kidney Int. 2000; 58: 691-700Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar). the response to hypoxia of is by the and activation of N. Morita N. Matsuda K. Watanabe M. Biochim. Biophys. Res. Commun. 1998; 249: 350-354Crossref PubMed Scopus (165) Google Scholar). the hypothesis that the pathways to cell proliferation in response to a specific stimulus be cell is on the MAP kinase pathways activated by hypoxia in a of to hypoxia-induced is of the that to MAP kinase activation and cell proliferation in response to is a family of has been shown that G can be activated by a of stimuli and in cell proliferation T. R.J. Rev. 1996; PubMed Scopus Google Scholar, N. Biol. 1998; PubMed Scopus Google Scholar). work in that specific of G for growth to a greater other and that cell in response to whereas the not A. R. Stenmark K.R. Biol. 1999; PubMed Scopus Google Scholar). activation of G has been to be a early in hypoxia-induced cell responses in different cell types Res. 2000; PubMed Scopus Google Scholar, D. Eur. J. Physiol. 1999; PubMed Scopus Google Scholar, N. J. A. Int. J. 1999; PubMed Scopus Google Scholar, H. H. 1998; PubMed Scopus Google Scholar). the of G in hypoxia-induced activation of MAP kinases and proliferative responses of vascular adventitial fibroblasts is We that hypoxia-induced proliferation of neonatal adventitial fibroblasts is through G activation of MAP kinases in a that is different from serum-induced MAP kinase activation and cell proliferation. hypoxia-induced signaling, a cell from hypoxia-induced fibroblast proliferation has been in (1Stenmark K.R. Mecham R.P. Annu. Rev. Physiol. 1997; 59: 89-144Crossref PubMed Scopus (294) Google Scholar). from were to serum for which of hypoxia-induced signaling in the absence of exogenous stimuli that influence the MAP kinase signaling an in which the effects of serum and hypoxia were in the and was to was a of MAP kinase signaling in hypoxia-induced proliferation. Eagle's minimum essential medium and were from bovine serum was from and for protein were from and and PD98059 were from for JNK1, and and and G were from was from was from SB202190 was from was from was from and DNA of JNK1 and and JNK2 and were from of the oligonucleotides are The on have on the of the and the are the Pertussis was from were from the pulmonary artery and of neonatal were and to the M. Stenmark K.R. Am. J. Physiol. 1995; Google Scholar). were in with and in a with was and were with and were The growth and of the were to were a of in to and with for to proliferative of exogenous growth factors. were to conditions or hypoxic conditions or in an in the of for DNA synthesis was as of M. Stenmark K.R. Am. J. Physiol. 1995; Google were as of hypoxic exposure, the were and hypoxia the serum-stimulated growth response of were in and to to the M. D. Stenmark K.R. Am. J. Respir. Cell Biol. 2000; PubMed Scopus Google Scholar). fibroblasts were to and hypoxia to The hypoxic were with the were as cell were in in medium and for with the of medium was to that the cell was and were to hypoxia for the and and were with the and M. D. Stenmark K.R. Am. J. Respir. Cell Biol. 2000; PubMed Scopus Google the and for was as cell were by a protein of protein were to on and to a The was with in for and with MAP kinase in with to activated MAP kinases were their pattern is is and is with were with with for The were by and the was on the of MAP kinases in response to hypoxic exposure and serum the adventitial fibroblasts were stimulated with for similar of time as The cell were for the and of MAP kinases by The protein for was by the with and with of from were on a and a of the was The were and the under the of was the in The time was as and increases in response to hypoxic exposure and serum were with to the oligonucleotides in this were oligonucleotides to a R. N. D. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). The transient of fibroblasts with and antisense was were with and to the cell the medium was with of JNK protein cell were with of protein was on and by with specific the proliferation fibroblasts were with of antisense and the of the medium was with with The was to the cells, and were to and or stimulated with for were for the of DNA synthesis to a M. Stenmark K.R. Am. J. Physiol. 1995; Google Scholar). the of and p38 MAP kinases in hypoxia-induced and serum-stimulated growth, fibroblasts were a of in for and for with PD98059 specific of ERK A.J. A. 1995; PubMed Scopus Google and SB202190 specific of p38 MAP kinase J. Biol. 1998; PubMed Scopus Google were to the medium and for The were to and hypoxia in the of for and for the of DNA synthesis M. Stenmark K.R. Am. J. Physiol. 1995; Google Scholar). the of G protein in proliferative responses of quiescent were with of for and to and hypoxia or stimulated with for in the of DNA synthesis was to the M. Stenmark K.R. Am. J. Physiol. 1995; Google Scholar). the of G protein in hypoxia-induced activation of MAP fibroblasts were with and to were with for the of cellular of protein were on by to and with and MAP kinase the were with are as the of in and of by the and of were were different the that hypoxia itself as a stimulus for fibroblasts from the of neonatal the of on DNA synthesis in fibroblasts in the absence of fibroblasts were to with of and for in the of and DNA synthesis was We found that of initiated a increase in in fibroblasts compared with hypoxia-induced increases in DNA synthesis in a increase in cell were to hypoxia because this is DNA synthesis was for and cell were increase in the of fibroblasts chronic exposure to hypoxia was found the hypoxia-induced proliferative response was to adventitial fibroblasts from the pulmonary compared the effects of hypoxia on DNA synthesis in fibroblast from the and the of adventitial fibroblasts from an increase in hypoxic exposure In in of increase in proliferation was in quiescent adventitial fibroblasts from the in response to in fibroblast hypoxia induced DNA synthesis to the as in adventitial fibroblasts hypoxia the serum-induced proliferative response of growth in the and absence of hypoxia were We found that the growth of fibroblasts in serum was under hypoxic conditions that hypoxia-induced and serum-stimulated growth of fibroblasts might be by distinct and signaling pathways in neonatal bovine adventitial In an to the that distinct signaling pathways are involved in hypoxia-induced growth responses of the effects of hypoxia on the activation of MAP kinase family members in fibroblasts and compared to induced by Hypoxia induced a and somewhat activation of and The pattern of activation was similar for and the magnitude of was greater for the time course of activation for hypoxia was similar to that for the magnitude of the activation was not as as serum fibroblasts had of and serum-stimulated in the protein of ERK kinases was in response to hypoxic exposure or serum for to that the increase in ERK in response to stimuli was not to an increase in ERK JNK was activated in fibroblasts hypoxic exposure JNK appeared to undergo a greater increase In serum-stimulated cells, JNK was also activated but the activation was to of the that the increase in of JNK in hypoxic fibroblasts was greater that of The increase in JNK in response to serum The increases in of JNK in response to serum and hypoxic exposure were and JNK that JNK protein in adventitial fibroblasts not hypoxia or serum exposure to the also found that hypoxia stimulated of p38 MAP kinase The hypoxia-induced activation of p38 MAP kinase was was to and to a increase in of p38 MAP kinase was in fibroblasts stimulated a of p38 MAP kinase that was also to The increases in induced by hypoxia and serum were and was of hypoxic exposure on p38 protein for to The p38 protein were and of serum in however, time was of the protein that hypoxia and serum ERK, JNK, and p38 MAP but are in the of activation of kinases the stimuli with the striking in p38 MAP kinase The hypoxia-induced increase in DNA synthesis in fibroblasts was attenuated by PD98059, a specific R. N. D. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google that the effects of PD98059 on DNA synthesis were and not caused by an of in quiescent the of with and PD98059 under and hypoxic conditions was by of the cell with and The of fibroblasts was not by PD98059 not that ERK activation is a necessary of the hypoxia-induced growth response of In the cells, serum-stimulated proliferation was by the of PD98059 the of ERK signaling pathways in the serum-stimulated growth response of of are not specific antisense oligonucleotides to of specific JNK and and to activation of JNK was to the hypoxia-induced proliferative response of fibroblasts A.J. A. 1995; PubMed Scopus Google Scholar). shown in the antisense oligonucleotides of JNK1 the increase in by fibroblasts in response to In the of adventitial fibroblasts their hypoxia-induced proliferative We that antisense oligonucleotides the of JNK1 by that JNK1 protein were in with the antisense oligonucleotides JNK1 antisense oligonucleotides not affect the of under or hypoxic conditions not The of JNK1 activation in serum-stimulated growth responses of fibroblasts was also the antisense growth was also attenuated by JNK1 antisense oligonucleotides to the of DNA synthesis with JNK1 antisense JNK2 antisense oligonucleotides appeared to the hypoxia-induced proliferative responses of fibroblasts In the increase in under hypoxic conditions was by JNK2 antisense oligonucleotides not the of p38 MAP kinase in hypoxia-induced and serum-stimulated proliferative responses of adventitial SB202190, a of p38 MAP kinase J. Biol. 1998; PubMed Scopus Google Scholar). of with SB202190 the hypoxia-induced increase in DNA synthesis that the inhibitory of SB202190 was to the of DNA synthesis but not to an increase in the of hypoxic fibroblasts were also in the and absence of The increase in induced by hypoxia was also by SB202190, thus the that the of DNA synthesis was to an of not In to the of hypoxia-induced growth by SB202190, the serum-stimulated proliferative response of fibroblasts was by a similar of the that activation of p38 MAP kinase has distinct in hypoxia-induced and serum-stimulated growth of We also hypoxia-induced activation patterns of ERK, JNK, and p38 MAP kinase in adventitial fibroblasts that the to in response to hypoxia increase in ERK and p38 MAP kinase activation was in in response to hypoxia a increase in JNK activation that was of lesser magnitude in induced to by hypoxia not the of in hypoxia-induced proliferative adventitial fibroblasts were with toxin, which activation by The hypoxia-induced increase in DNA synthesis was markedly attenuated by in response to serum was also attenuated by an important for Gαi/o activation in hypoxia-induced and serum-stimulated growth responses of neonatal adventitial the inhibitory effects of on hypoxia-induced proliferation were through of MAP quiescent fibroblasts were with and to and MAP kinase activation was activated of the The hypoxia-induced activation of ERK and JNK was by In of fibroblasts with for had on the hypoxia-induced of p38 MAP kinase hypoxia ERK and JNK through the activation of Gαi/o whereas hypoxia-induced activation of p38 MAP kinase occurs through other G or other as The that hypoxia can stimulate quiescent neonatal adventitial fibroblasts to in the absence of exogenous mitogens and that this proliferative response is in on Gαi/o-mediated activation of ERK and JNK pathways and activation of p38 MAP kinase. as important is the that not adventitial fibroblast the of in response to hypoxia and that in the hypoxia not stimulate ERK or p38 We that the hypoxia-induced proliferative response to be through different activated the are stimulated to with was by activation patterns of ERK, JNK and p38 MAP kinases were different in response to ERK, and JNK1 nearly ablated the proliferative response induced by hypoxia had effects on serum-induced p38 MAP kinase with SB202190 attenuated hypoxia-induced proliferation led to an increase in serum-induced and hypoxia led to of serum-induced have patterns of activation of ERK, JNK, and p38 MAP kinase in response to hypoxia on the cell and the conditions under which the were et (10Seko Y. Tobe K. Ueki K. Kadowaki T. Tazaki Y. Circ. Res. 1996; 78: 82-90Crossref PubMed Scopus (112) Google Scholar, 11Seko Y. Takahashi N. Tobe K. Kadowaki T. Yazaki Y. Biochim. Biophys. Acta. 1997; 239: 840-844Google that hypoxia and ERK as as JNK and p38 MAP kinase in the of hypoxia-induced activation of MAP kinases in was not has been that hypoxia JNK and p38 MAP kinase and proliferation in bovine adventitial fibroblasts P.H. Paul A. Belham C.M. Peacock A.J. Wadsworth R.M. Gould G.W. Welsh D. Plevin R. Am. J. Respir. Crit Care Med. 1998; 158: 958-962Crossref PubMed Scopus (47) Google Scholar, Plevin R. Wadsworth R. Peacock A.J. Am. J. Respir. Crit. Care Med. 1998; 158: PubMed Scopus Google Scholar). in hypoxia has on In cells, hypoxia has been shown to ERK and p38 MAP kinase but not JNK K.R. Mendonca H.L. Calaoagan J.M. Knapp A.M. Giaccia A.J. Strok P.J.S. J. Biol. Chem. 1999; 274: 12890-12897Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar). a complex of signaling pathways in the regulation of cellular responses hypoxic exposure that is cell and the of serum for hypoxic exposure, was to of MAP kinase signaling in the absence of MAP kinase was induced by hypoxia in that were also stimulated to In other cells, also from the of neonatal hypoxia not proliferation, and MAP kinase was not the that subsets of adventitial fibroblasts that different to MAP kinase activation by We have a and dramatic activation of ERK in neonatal bovine fibroblasts that were stimulated to with with that kinases are for proliferation in a of cell types K. 2000; PubMed Scopus Google Scholar). A activation of compared with was in response to under the a greater of A of activated has been shown to be with proliferation in 1997; PubMed Scopus Google hypothesis that activation of ERK might be necessary for hypoxia-induced proliferation in The pattern of ERK activation was similar to that under serum in magnitude. In of ERK activation hypoxic exposure the hypoxia-induced proliferative responses of In serum-stimulated growth of fibroblasts was by the of ERK are with the that a in hypoxia-induced proliferative response in serum-induced In activation of JNK of hypoxic is in fibroblasts activation of JNK in response to hypoxia was not of hypoxic exposure P.H. Paul A. Belham C.M. Peacock A.J. Wadsworth R.M. Gould G.W. Welsh D. Plevin R. Am. J. Respir. Crit Care Med. 1998; 158: 958-962Crossref PubMed Scopus (47) Google Scholar). the time course of JNK activation in response to hypoxia in is with that of the growth different JNK and and different with and that JNK to a greater growth promoting factors, including JNK Watanabe R.J. M. 1996; Google Scholar). have that this is involved in growth K. A. T. D. 2000; PubMed Scopus Google Scholar). antisense that JNK1 activation in response to hypoxia and serum effects on cell proliferation, with other a for JNK1 in proliferation A.J. A. 1995; PubMed Scopus Google Scholar, 1997; PubMed Google Scholar, Y. D. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). In the JNK2 antisense that JNK2 might negative effects on hypoxia-induced cell of JNK have also been in cell J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). is that hypoxia and negative growth pathways as a growth and that are components of this response. We found a increase in p38 MAP kinase in response to The activation pattern of p38 MAP kinase was different that for ERK and JNK and different from the activation pattern induced by The of have that p38 is involved in growth 1995; Full Text PDF PubMed Scopus Google Scholar, M. J. R.J. 1995; 270: PubMed Scopus Google Scholar). a have for this kinase in promoting cell Y. H. J. K.R. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google ischemic D. R. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google and J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google and cell proliferation or J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, Y. Takahashi N. R.J. K. 1998; PubMed Google Scholar). with the of SB202190, of hypoxia-induced proliferative responses of neonatal fibroblasts are with of the of p38 MAP kinase in the hypoxia-induced proliferative response of fibroblasts and C.P. Batlle D. Sahai A. Kidney Int. 2000; 58: 691-700Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, Plevin R. Wadsworth R. Peacock A.J. Am. J. Respir. Crit. Care Med. 1998; 158: PubMed Scopus Google Scholar). The that the of SB202190 that attenuated hypoxia-induced proliferation augmented serum-induced proliferation also for p38 in hypoxic cell responses. The p38 family of protein kinases of including and Cell Biol. 1997; Full Text PDF PubMed Scopus Google Scholar). The SB202190, is nearly and but not or R.J. Biophys. Res. Commun. 1997; PubMed Scopus Google Scholar). the inhibitory effects of SB202190 on the hypoxia-induced growth response of fibroblasts that activation of p38 might an important in hypoxic growth responses of activation of and in response to hypoxia has also been in J. D. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). be the specific activation patterns of p38 MAP kinase and their in cellular responses hypoxic exposure in neonatal adventitial Little is of the necessary for MAP kinase activation in response to In cell hypoxia activation of in a D. A. D. Giaccia A.J. 2000; PubMed Google Scholar). in and have hypoxia-induced activation of G as an early in the of and cell Res. 2000; PubMed Scopus Google Scholar, D. Eur. J. Physiol. 1999; PubMed Scopus Google Scholar, N. J. A. Int. J. 1999; PubMed Scopus Google Scholar, H. H. 1998; PubMed Scopus Google Scholar). have been shown to be involved in responses and to be activated by stresses such as and N. N. Am. J. Respir. Cell Biol. 2000; PubMed Scopus Google Scholar, T. R.J. Rev. 1996; PubMed Scopus Google Scholar, M. Y. R. K. T. H. 2000; PubMed Scopus Google Scholar). have also that of vascular wall Gαi/o to a greater for proliferative responses N. Biol. 1998; PubMed Scopus Google Scholar). with toxin, which signaling through the hypothesis that activation of Gαi/o is necessary for hypoxia-induced proliferation. also that hypoxic activation of ERK and JNK is through but the activation of p38 MAP kinase occurs of this is that hypoxia might also G or and hypoxia-induced activation of p38 MAP kinase might be through G proteins. of G in hypoxia-induced activation of MAP kinases is with the that activation of ERK but not p38 MAP kinase to be dependent in on of by fibroblasts under H. Cell Res. 2000; PubMed Scopus Google Scholar). of the has also been shown to be to activation of ERK and p38 by and K. H. N. Y. H. T. R. K. Y. J. 1999; PubMed Scopus Google Scholar). Pertussis G have also been in activation of ERK in and to changes in Circ. Res. 1996; PubMed Scopus Google Scholar, Cell 2000; PubMed Scopus Google Scholar). that Gαi/o are a necessary of hypoxia-induced proliferation in neonatal that hypoxia in the absence of exogenous MAP kinase activation and cell proliferation the that G protein activation and cellular in a is with of et M. Y. R. K. T. H. 2000; PubMed Scopus Google found that the ERK activation induced by is of to work be the pathways through which hypoxia G proteins. In have shown that hypoxia proliferation of adventitial fibroblast from neonatal in the absence of proliferation is by as is the activation of ERK and JNK, an of Gαi/o in hypoxic growth the MAP kinase signaling pathways induced by p38 MAP distinct from that induced by or with growth factors under the of different of of which are of a hypoxic stimulus a proliferative response. We and for bovine pulmonary artery for for of this and for the antisense