Hypoxia-responsive growth factors upregulate periostin and osteopontin expression via distinct signaling pathways in rat pulmonary arterial smooth muscle cells.
This study tested the hypothesis that expression of the novel adhesion molecule periostin (PN) and osteopontin (OPN) is increased in lung and in isolated pulmonary arterial smooth muscle cells (PASMCs) in response to the stress of hypoxia and explored the signaling pathways involved. Adult male rats were exposed to 10% O2 for 2 wk, and growth-arrested rat PASMCs were incubated under 1% O2 for 24 h. Hypoxia increased PN and OPN mRNA expression in rat lung. In PASMCs, hypoxia increased PN but not OPN expression. The hypoxia-responsive growth factors fibroblast growth factor-1 (FGF-1) and angiotensin II (ANG II) caused dose- and time-dependent increases in PN and OPN expression in PASMCs. FGF-1-induced PN expression was blocked by the FGF-1 receptor antagonist PD-166866 and by inhibitors of phosphatidylinositol 3-kinase (PI3K) (LY-294002, wortmannin), p70S6K (rapamycin), MEK1/2 (U-0126, PD-98059), and p38MAPK (SB-203580) but not of JNK (SP-600125). ANG II-induced PN expression was blocked by the AT(1)-receptor antagonist losartan and by inhibitors of PI3K and MEK1/2. In contrast, FGF-1-induced OPN expression was blocked by inhibitors of JNK or MEK1/2 but not of PI3K, p70S6K, or p38MAPK. Activation of p70S6K and p38MAPK by anisomycin robustly stimulated PN but not OPN expression. This study is the first to demonstrate that growth factor-induced expression of PN in PASMCs is mediated through PI3K/p70S6K, Ras/MEK1/2, and Ras/p38MAPK signaling pathways, whereas the expression of OPN is mediated through Ras/MEK1/2 and Ras/JNK signaling pathways. These differences in signaling suggest that PN and OPN may play different roles in pulmonary vascular remodeling under pathophysiological conditions.
Li
Peng
P
Vascular Biology and Hypertension Program, Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
Oparil
Suzanne
S
Feng
Wenguang
W
Chen
Yiu-Fai
YF
D000818:Animals; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002478:Cells, Cultured; D006133:Growth Substances / Q000494:pharmacology*; D000860:Hypoxia / Q000378:metabolism*; D008168:Lung / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D053495:Osteopontin; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012038:Regeneration / Q000187:drug effects / Q000502:physiology; D012795:Sialoglycoproteins / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation / Q000187:drug effects
D015815:Cell Adhesion Molecules; D006133:Growth Substances; C512836:Postn protein, rat; D012795:Sialoglycoproteins; C506896:Spp1 protein, mouse; C506897:Spp1 protein, rat; D053495:Osteopontin