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A7394 - Endothelial and Smooth Muscle Cell Interaction Mediates Vascular Remodeling and Pulmonary Arterial Hypertension
Author Block: Z. Dai, M. M. Zhu, Y. Peng, H. Jin, X. Zhang, Y. Zhao; Pediatrics, Northwestern University, Chicago, IL, United States.
Rationale: Angioproliferative vasculopathy is a hallmark of pulmonary arterial hypertension (PAH). However, little is known how endothelial cell (EC) and smooth muscle cell (SMC) crosstalk regulates the angioproliferative vascular remodeling. Objectives: We aimed to investigate the role of EC and SMC interaction and underlying signaling pathways in the development of PAH.Methods: SMC-specific Foxm1 and Cxcr4 knockout mice, EC-specific Foxm1 and Egln1 knockout mice, as well as EC-specific Egln1 and Cxcl12 double knockout mice were used to assess the role of FoxM1 on SMC proliferation and PH. Human pulmonary SMCs were transfected with siRNA and treated with angiocrine factors. FoxM1 inhibitor Thiostrepton was used in Sugen 5416/hypoxia- and monocrotaline-challenged rats.Results: FoxM1 expression was markedly upregulated in the lungs of idiopathic PAH patients and 4 discrete PH rodent models. Mice with SMC- (but not EC-) specific deletion of Foxm1 were protected from hypoxia- or Sugen 5416/hypoxia-induced PH. The upregulation of FoxM1 in SMCs induced by multiple EC-derived angiocrine factors (PDGF-B, CXCL12, ET-1 and MIF) mediated SMC proliferation. Genetic deletion of endothelial Cxcl12 in Egln1Tie2Cre mice or loss of its cognate receptor Cxcr4 in SMCs in hypoxia-treated mice inhibited FoxM1 expression, SMC proliferation and PH. Accordingly, pharmacological inhibition of FoxM1 inhibited severe PH in both Sugen 5416/hypoxia and monocrotaline-challenged rats. Conclusions. Angiocrine factors derived from dysfunctional ECs induced expression of FoxM1 in SMCs and activated FoxM1-dependent SMC proliferation which contributes to pulmonary vascular remodeling and PH. Thus, targeting FoxM1 signaling represents a novel strategy for treatment of PAH.