Exploring Integrin α5β1 as a Potential Therapeutic Target for Pulmonary Arterial Hypertension: Insights From Comprehensive Multicenter Preclinical Studies

作者：Sarah‐Eve Lemay, Mónica S. Montesinos, Yann Grobs, Tetsuro Yokokawa, Tsukasa Shimauchi, Manon Mougin, Charlotte Romanet, Mélanie Sauvaget, Sandra Breuils‐Bonnet, Alice Bourgeois, Charlie Théberge, Andréanne Pelletier, Reem El Kabbout, Sandra Martineau, Keiko Yamamoto, Muzaffar Akram, Adrian S. Ray, Blaise Lippa, Bryan Goodwin, Fu‐Yang Lin, Hua Wang, James J. Dowling, Min Lü, Qiao Qi, T. Andrew McTeague, Terence I. Moy, François Potus, Steeve Provencher, Olivier Boucherat, Sébastien Bonnet · 发表于：Circulation · 年份：2025 · DOI：10.1161/circulationaha.124.070693 · 被引用次数：28 · 研究领域：Pulmonary Hypertension Research and Treatments、Cell Adhesion Molecules Research、Proteoglycans and glycosaminoglycans research

BACKGROUND: Pulmonary arterial hypertension (PAH) is characterized by obliterative vascular remodeling of the small pulmonary arteries (PAs) and progressive increase in pulmonary vascular resistance leading to right ventricular failure. Although several drugs are approved for the treatment of PAH, mortality rates remain high. Accumulating evidence supports a pathological function of integrins in vessel remodeling, which are gaining renewed interest as drug targets. However, their role in PAH remains largely unexplored. METHODS: The expression of the RGD (arginylglycylaspartic acid)-binding integrin α5β1 was assessed in PAs, PA smooth muscle cells, and PA endothelial cells from patients with PAH and controls using NanoString, immunoblotting, and Mesoscale Discovery assays. RNA sequencing was conducted to identify gene networks regulated by α5β1 inhibition in PAH PA smooth muscle cells. The therapeutic efficacy of α5β1 inhibition was evaluated using a novel small molecule inhibitor and selective neutralizing antibodies in Sugen/hypoxia and monocrotaline rat models, with validation by an external contract research organization. Comparisons were made against standard-of-care therapies (ie, macitentan, tadalafil) and sotatercept and efficacy was assessed using echocardiographic, hemodynamic, and histological assessments. Ex vivo studies using human precision-cut lung slices were performed to further assess the effects of α5β1 inhibition on pulmonary vascular remodeling. RESULTS: W...