Conference: 2018 PHA International PH Conference & Scientific Sessions
Release Date: 07.28.2018
Presentation Type: Abstracts
File Download: Conference 2018_1004
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Abstract presented at the 2018 International PH Conference and Scientific Sessions in Orlando, Fla., June 28-July 1, 2018.
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. We aimed to investigate the role of EC and SMC interaction and underlying signaling pathways in the development of PAH.
SMC-specific Foxm1 or Cxcr4 knockout mice, EC-specific Foxm1 or Egln1 knockout mice, as well as EC-specific Egln1/Cxcl12 double knockout mice were used to assess the role of FoxM1 on SMC proliferation and PH. Lung tissues and cells from PAH patients were employed to validate clinical relevance. FoxM1 inhibitor Thiostrepton was used in Sugen 5416/hypoxia- and monocrotaline-challenged rats.
FoxM1 expression was markedly upregulated in lungs and pulmonary arterial SMCs 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 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.
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.
Figure 1: Activation of FoxM1 signaling in lungs of IPAH patients and PH mice and rats.
Figure 2: Foxm1 disruption in SMCs inhibits SuHx-induced PH in mice
Figure 3: Endothelial and smooth muscle cell interaction mediate FoxM1 upregulation, SMC proliferation and PH
Figure 4: Pharmacological inhibition of FoxM1 inhibits both SuHx and MCT-induced PH in rats.