Targeting cell motility in pulmonary arterial hypertension

Abstract

Pulmonary artery smooth muscle cells (PASMC), in pulmonary arterial hypertension (PAH), contribute to obliterative vascular remodelling and are characterised by enhanced proliferation, suppressed apoptosis and, a much less studied, increased migration potential. One of the major proteins that regulate cell migration is focal adhesion kinase (FAK), but its role in PAH is not fully understood. We hypothesised that targeting cell migration by FAK inhibition may be a new therapeutic strategy in PAH.In vivo, inhalation of FAK-siRNA (n55) or oral delivery of PF-228 (FAK inhibitor PF-573 228; n55) inhibited rat monocrotaline induced PAH, improving the haemodynamics, vascular remodelling (media thickness), and right ventricular hypertrophy. In vitro, FAK was activated in PAH human lungs (n58) or PASMC when compared to those form healthy subjects (Western blot, n55), in a Src-dependent manner, as it was reversed by the specific Src inhibitor PP2. The degree of FAK phosphorylation at Y576 correlated positively with pulmonary vascular resistance in PAH patients. FAK inhibition (siRNA, PF-228 and PP2) in PAH-PASMCs induced a fivefold increase in apoptosis (percentage of terminal deoxynucleotidyl transferase dUTP nick end labelling), a 2.5-fold decrease in proliferation (%Ki67), an 18% decrease in cell migration (colorimetric assay) and a 50% decrease in cell invasion (wound healing).Suppressing PASMC migration by FAK inhibition inhibits PAH progression and may open a new therapeutic window in PAH.

Galectin-3- Mediated Transdifferentiation of Pulmonary Artery Endothelial Cells Contributes to Hypoxic Pulmonary Vascular Remodeling

“…In PAH, the elevation of pulmonary arterial pressure is due to a combination of sustained vasoconstriction and structural remodeling, significant components of remodeling in PAH include medial thickening in muscularized pulmonary vessels, as well as extension of muscularization distally to small pulmonary arteries [33][34], both of which are associated with enhanced proliferation [35] and migration [36] of PASMCs. The sources of PASMCs may be proliferation or another type of cell transformation.…”

Apolipoprotein A-I Mimetic Peptide 4F Rescues Pulmonary Hypertension by Inducing MicroRNA-193-3p

“…PAH is a clinical condition associated with severe pulmonary vascular disorder due to excessive proliferation of pulmonary artery smooth muscle and endothelial cells, migration of pulmonary vascular smooth muscle cells 2 , remodelling of small pulmonary arteries with diminished apoptosis, enhanced inflammation and fibrosis in the lung tissue 3 . Vascular disorders result from complex interactions between oxidized lipoproteins, monocytes/macrophages, and injured endothelium and smooth muscle cells.…”

Translational research in pulmonary hypertension: challenge and opportunity

“…The article by PAULIN et al [6] focuses on FAK, a broadly expressed non-receptor kinase, which is a key participant in a range of cell functions, including cell adhesion, migration, proliferation and survival [17], contributing to angiogenesis, wound healing, cardiac hypertrophy and tissue fibrosis [18]. The current model for FAK signalling shows that FAK activation is triggered by integrin-dependent cell adhesion, by growth factor receptor activation or activation of G protein-coupled receptors [17].…”

“…The current model for FAK signalling shows that FAK activation is triggered by integrin-dependent cell adhesion, by growth factor receptor activation or activation of G protein-coupled receptors [17]. Whereas UMAR et al [19] previously reported activation of FAK in the right ventricle of monocrotaline-induced pulmonary hypertensive rats [19], PAULIN et al [6] concentrated on pulmonary vascular remodelling and on a proofof-concept inhibition of FAK. Postulating that FAK may function as a signalling hub, they treated rats with established monocrotaline-induced pulmonary hypertension either with a single inhalation of FAK-small interfering RNA or oral treatment with a FAK inhibitor.…”

“…In parallel, experimental and mechanistic animal and cell studies are now published every week. The article in this issue of the European Respiratory Journal by PAULIN et al [6] on the inhibition of the focal adhesion kinase (FAK) in a rat model of pulmonary hypertension merits attention and comment.…”