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Objective-Despite modern therapies, pulmonary arterial hypertension (PAH) harbors a high mortality. Vascular remodeling is a hallmark of the disease. Recent clinical studies revealed that antiremodeling approaches with tyrosine-kinase inhibitors such as imatinib are effective, but its applicability is limited by significant side effects. Although imatinib has multiple targets, expression analyses support a role for platelet-derived growth factor (PDGF) in the pathobiology of the disease. However, its precise role and downstream signaling events have not been established. Approach and Results-Patients with PAH exhibit enhanced expression and phosphorylation of β PDGF receptor (βPDGFR) in remodeled pulmonary arterioles, particularly at the binding sites for phophatidyl-inositol-3-kinase and PLCγ at tyrosine residues 751 and 1021, respectively. These signaling molecules were identified as critical downstream mediators of βPDGFR-mediated proliferation and migration of pulmonary arterial smooth muscle cells. We, therefore, investigated mice expressing a mutated βPDGFR that is unable to recruit phophatidyl-inositol-3-kinase and PLCγ (βPDGFR F3/F3 ). PDGF-dependent Erk1/2 and Akt phosphorylation, cyclin D1 induction, and proliferation, migration, and protection against apoptosis were abolished in βPDGFR F3/F3 pulmonary arterial smooth muscle cells. On exposure to chronic hypoxia, vascular remodeling of pulmonary arteries was blunted in βPDGFR F3/F3 mice compared with wild-type littermates. These alterations led to protection from hypoxia-induced PAH and right ventricular hypertrophy. Conclusions-By means of a genetic approach, our data provide definite evidence that the activated βPDGFR is a key contributor to pulmonary vascular remodeling and PAH. Selective disruption of PDGF-dependent phophatidyl-inositol-3-kinase and PLCγ activity is sufficient to abolish these pathogenic responses in vivo, identifying these signaling events as valuable targets for antiremodeling strategies in PAH. From the Klinik III für Innere Medizin, Herzzentrum der Universität zu Köln, Cologne, Germany (H.t.F., E.M.B., M.L., M.Z., A.K., M.V., E.C., T.K., S.B., S.R.); Center for Molecular Medicine Cologne (CMMC) (H.t.F., E.M.B., M.L., M.Z., A.K., M.V., E.C., S.B., S.R.), and Cologne Cardiovascular Research Center (CCRC) (H.t.F., A.K., S.B., S.R.), University of Cologne, Cologne, Germany; University of Giessen and Marburg Lung Center (UGMLC), Giessen, Germany (W.J., K.M., R.T.S.); and Center for Cardiovascular Research, University of Hawaii, Honolulu (M.D.T. 10,11 Data from atherosclerosis and restenosis models support an important role of PDGF in vivo. 12,13 In the context of PAH, several studies reporting expression analyses and pharmacological interventions suggest a role for PDGF in experimental and human disease, [14][15][16][17][18][19][20] but its precise role and downstream signaling remain to be established.Inhibition of PDGFR signaling may be achieved by tyrosine kinase inhibitors, such as imatinib mesylate, which was developed for the...

Objective— Neointima formation after vascular injury remains a significant problem in clinical cardiology, and current preventive strategies are suboptimal. Phosphatidylinositol 3′-kinase is a central downstream mediator of growth factor signaling, but the role of phosphatidylinositol 3′-kinase isoforms in vascular remodeling remains elusive. We sought to systematically characterize the precise role of catalytic class IA phosphatidylinositol 3′-kinase isoforms (p110α, p110β, p110δ), which signal downstream of receptor tyrosine kinases, for vascular remodeling in vivo. Approach and Results— Western blot analyses revealed that all 3 isoforms are abundantly expressed in smooth muscle cells. To analyze their significance for receptor tyrosine kinases–dependent cellular responses, we used targeted gene knockdown and isoform-specific small molecule inhibitors of p110α (PIK-75), p110β (TGX-221), and p110δ (IC-87114), respectively. We identified p110α to be crucial for receptor tyrosine kinases signaling, thus affecting proliferation, migration, and survival of rat, murine, and human smooth muscle cells, whereas p110β and p110δ activities were dispensable. Surprisingly, p110δ exerted noncatalytic functions in smooth muscle cell proliferation, but had no effect on migration. Based on these results, we generated a mouse model of smooth muscle cell–specific p110α deficiency (sm-p110α −/− ). Targeted deletion of p110α in sm-p110α −/− mice blunted growth factor–induced cellular responses and abolished neointima formation after balloon injury of the carotid artery in mice. In contrast, p110δ deficiency did not affect vascular remodeling in vivo. Conclusions— Receptor tyrosine kinases–induced phosphatidylinositol 3′-kinase signaling via the p110α isoform plays a central role for vascular remodeling in vivo. Thus, p110α represents a selective target for the prevention of neointima formation after vascular injury, whereas p110β and p110δ expression and activity do not play a significant role.

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