A critical role for p130Cas in the progression of pulmonary hypertension in humans and rodents.
BACKGROUND
Pulmonary arterial hypertension (PAH) is a progressive and fatal disease characterized by pulmonary arterial muscularization due to excessive pulmonary vascular cell proliferation and migration, a phenotype dependent upon growth factors and activation of receptor tyrosine kinases (RTKs). p130(Cas) is an adaptor protein involved in several cellular signaling pathways that control cell migration, proliferation, and survival.


OBJECTIVE
We hypothesized that in experimental and human PAH p130(Cas) signaling is overactivated, thereby facilitating the intracellular transmission of signal induced by fibroblast growth factor (FGF)2, epidermal growth factor (EGF), and platelet-derived growth factor (PDGF).


RESULTS
In patients with PAH, levels of p130(Cas) protein and/or activity are higher in the serum, in the walls of distal pulmonary arteries, in cultured smooth muscle cells (PA-SMCs), and in pulmonary endothelial cells (P-ECs) than in control subjects. These abnormalities in the p130(Cas) signaling were also found in the chronically hypoxic mice and monocrotaline-injected rats as models of human PAH. We obtained evidence for the convergence and amplification of the growth-stimulating effect of the EGF-, FGF2-, and PDGF-signaling pathways via the p130(Cas) signaling pathway. We found that daily treatment with the EGF-R inhibitor gefitinib, the FGF-R inhibitor dovitinib, and the PDGF-R inhibitor imatinib started 2 weeks after a subcutaneous monocrotaline injection substantially attenuated the abnormal increase in p130(Cas) and ERK1/2 activation and regressed established pulmonary hypertension.


CONCLUSIONS
Our findings demonstrate that p130(Cas) signaling plays a critical role in experimental and idiopathic PAH by modulating pulmonary vascular cell migration and proliferation and by acting as an amplifier of RTK downstream signals.
INSERM UMR 999, Centre Chirurgical Marie Lannelongue, 133 Avenue de la Resistance, Le Plessis-Robinson, France.
Ly
L
Tu
Frances S
FS
De Man
Barbara
B
Girerd
Alice
A
Huertas
Marie-Camille
MC
Chaumais
Florence
F
Lecerf
Charlène
C
François
Frédéric
F
Perros
Peter
P
Dorfmüller
Elie
E
Fadel
David
D
Montani
Saadia
S
Eddahibi
Marc
M
Humbert
Christophe
C
Guignabert
D000818:Animals; D001549:Benzamides; D001562:Benzimidazoles / Q000627:therapeutic use; D016022:Case-Control Studies; D050719:Crk-Associated Substrate Protein / Q000378:metabolism*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000378:metabolism; D065627:Familial Primary Pulmonary Hypertension; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D000077156:Gefitinib; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D000068877:Imatinib Mesylate; D051379:Mice; D016686:Monocrotaline; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D010879:Piperazines / Q000627:therapeutic use; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011651:Pulmonary Artery / Q000378:metabolism; D011743:Pyrimidines / Q000627:therapeutic use; D011799:Quinazolines / Q000627:therapeutic use; D015363:Quinolones / Q000627:therapeutic use; D051381:Rats; D015398:Signal Transduction / Q000502:physiology
C500007:4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one; C493841:BCAR1 protein, human; D001549:Benzamides; D001562:Benzimidazoles; D050719:Crk-Associated Substrate Protein; D010879:Piperazines; D010982:Platelet-Derived Growth Factor; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011799:Quinazolines; D015363:Quinolones; D016222:Fibroblast Growth Factor 2; D004815:Epidermal Growth Factor; D016686:Monocrotaline; D000068877:Imatinib Mesylate; D000077156:Gefitinib