Hypoxia-induced proliferative response of vascular adventitial fibroblastsis dependent on G protein-mediated activation of mitogen-activated proteinkinases
M. Das et al., Hypoxia-induced proliferative response of vascular adventitial fibroblastsis dependent on G protein-mediated activation of mitogen-activated proteinkinases, J BIOL CHEM, 276(19), 2001, pp. 15631-15640
Hypoxia has been shown to act as a proliferative stimulus for adventitial f
ibroblasts of the pulmonary artery. The signaling pathways involved in this
growth response, however, remain unclear. We tested the hypothesis that hy
poxia-induced proliferation of fibroblasts would be dependent on distinct (
compared with serum) activation and utilization patterns of mitogen-activat
ed protein (MAP) kinases initiated by G alpha (i/o) proteins. We found that
hypoxia stimulated increases in DNA synthesis and growth of quiescent fibr
oblasts in the absence of exogenous mitogens and also markedly augmented se
rum-stimulated growth responses. Hypoxia caused a transient activation of e
xtracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK
), the time course and pattern of which was somewhat similar to that induce
d by serum but which was of lesser magnitude. On the other hand, hypoxia-in
duced activation of p38 MAP kinase was biphasic, whereas serum-stimulated a
ctivation of p38 MAP kinase was transient, and the magnitude of activation
was greater for hypoxia compared with that of serum stimulation. ERK1/2, JN
K1, and p38 MAP kinase but not JNK2 were necessary for hypoxia-induced prol
iferation because PD98059, SB202190, and JNK1 antisense oligonucleotides ne
arly ablated the growth response. JNK2; appeared to act as a negative modul
ator 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, where
as SB202190 led to an increase in DNA synthesis. Pertussis toxin, which blo
cks G alpha (i/o)-mediated signaling, markedly attenuated hypoxia-induced D
NA synthesis and activation of ERK and JNK but not p38 MAP kinase, We concl
ude that hypoxia itself can act as a growth promoting stimulus for subsets
of bovine neonatal adventitial fibroblasts largely through G alpha (i/o)-me
diated activation of a complex network of MAP kinases whose specific contri
butions to hypoxia-induced proliferation differ from traditional serum-indu
ced growth signals.