Exploring Integrin α5β1 as a Potential Therapeutic Target for Pulmonary Arterial Hypertension: Insights From Comprehensive Multicenter Preclinical Studies
Abstract
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: We found that the arginine-glycine-aspartate RGD-binding integrin α5β1 is upregulated in PA endothelial cells and PA smooth muscle cells from patients with PAH and remodeled PAs from animal models. Blockade of the integrin α5β1 or depletion of the α5 subunit downregulated FOXM1 (forkhead box protein M1)–regulated gene networks, resulting in mitotic defects and inhibition of the pro-proliferative and apoptosis-resistant phenotype of PAH cells. We demonstrated that α5β1 integrin blockade safely attenuates pulmonary vascular remodeling and improves hemodynamics and right ventricular function and matched or exceeded the efficacy of standard of care and sotatercept in multiple preclinical models. Ex vivo studies further validated its potential in reversing advanced remodeling in human precision-cut lung slices. CONCLUSIONS: These findings establish α5β1 integrin as a pivotal driver of PAH pathology and we propose its inhibition as a novel, safe, and effective therapeutic strategy for PAH.
Article Details
Authors (30)
Sarah-Eve Lemay
Pulmonary Hypertension and Vascular Biology Research Group CRIUCPQ, Department of Medicine, Laval University, Quebec, Canada (S.B., S.P., S.B.-B., S.-E.L.).
Mónica S. Montesinos
Morphic Therapeutic, Inc, Waltham, MA (M.S.M., M.A., A.S.R., B.L., B.G., F.-Y.L., H.W., J.E.D., M.L., Q.Q., T.A.M., T.I.M.).
Yann Grobs
Tetsuro Yokokawa
Fukushima Medical University, Fukushima, Japan
Tsukasa Shimauchi
Pulmonary Hypertension Research Group, Québec Heart and Lung Institute Research Center, Quebec City, QC, Canada (S.-E.L., Y.G., T.Y., T.S., M.M., C.R., M.S., S.B.-B., A.B., C.T., A.P., R.E.K., S.M., K.Y., F.P., S.P., O.B., S.B.).
Manon Mougin
Charlotte Romanet
Pulmonary Hypertension Research Group, Québec Heart and Lung Institute Research Center, Quebec City, QC, Canada (S.-E.L., Y.G., T.Y., T.S., M.M., C.R., M.S., S.B.-B., A.B., C.T., A.P., R.E.K., S.M., K.Y., F.P., S.P., O.B., S.B.).
Mélanie Sauvaget
Pulmonary Hypertension Research Group, Québec Heart and Lung Institute Research Center, Quebec City, QC, Canada (S.-E.L., Y.G., T.Y., T.S., M.M., C.R., M.S., S.B.-B., A.B., C.T., A.P., R.E.K., S.M., K.Y., F.P., S.P., O.B., S.B.).
Sandra Breuils-Bonnet
Alice Bourgeois
CRIUCPQ, Quebec, Quebec, Canada
Charlie Théberge
Pulmonary Hypertension Research Group, Québec Heart and Lung Institute Research Center, Quebec City, QC, Canada (S.-E.L., Y.G., T.Y., T.S., M.M., C.R., M.S., S.B.-B., A.B., C.T., A.P., R.E.K., S.M., K.Y., F.P., S.P., O.B., S.B.).
Andréanne Pelletier
Pulmonary Hypertension Research Group, Québec Heart and Lung Institute Research Center, Quebec City, QC, Canada (S.-E.L., Y.G., T.Y., T.S., M.M., C.R., M.S., S.B.-B., A.B., C.T., A.P., R.E.K., S.M., K.Y., F.P., S.P., O.B., S.B.).
Reem El Kabbout
Sandra Martineau
Keiko Yamamoto
Pulmonary Hypertension Research Group, Québec Heart and Lung Institute Research Center, Quebec City, QC, Canada (S.-E.L., Y.G., T.Y., T.S., M.M., C.R., M.S., S.B.-B., A.B., C.T., A.P., R.E.K., S.M., K.Y., F.P., S.P., O.B., S.B.).
Muzaffar Akram
Morphic Therapeutic, Inc, Waltham, MA (M.S.M., M.A., A.S.R., B.L., B.G., F.-Y.L., H.W., J.E.D., M.L., Q.Q., T.A.M., T.I.M.).
Adrian S. Ray
Morphic Therapeutic, Inc, Waltham, MA (M.S.M., M.A., A.S.R., B.L., B.G., F.-Y.L., H.W., J.E.D., M.L., Q.Q., T.A.M., T.I.M.).
Blaise Lippa
Morphic Therapeutic, Inc, Waltham, MA (M.S.M., M.A., A.S.R., B.L., B.G., F.-Y.L., H.W., J.E.D., M.L., Q.Q., T.A.M., T.I.M.).
Bryan Goodwin
Morphic Therapeutic, Inc, Waltham, MA (M.S.M., M.A., A.S.R., B.L., B.G., F.-Y.L., H.W., J.E.D., M.L., Q.Q., T.A.M., T.I.M.).
Fu-Yang Lin
Morphic Therapeutic, Inc, Waltham, MA (M.S.M., M.A., A.S.R., B.L., B.G., F.-Y.L., H.W., J.E.D., M.L., Q.Q., T.A.M., T.I.M.).
Hua Wang
James E. Dowling
Morphic Therapeutic, Inc, Waltham, MA (M.S.M., M.A., A.S.R., B.L., B.G., F.-Y.L., H.W., J.E.D., M.L., Q.Q., T.A.M., T.I.M.).
Min Lu
College of Chemistry and Chemical Engineering, Frontiers Science Center for Rare Isotopes
Qi Qiao
T. Andrew McTeague
Morphic Therapeutic, Inc, Waltham, MA (M.S.M., M.A., A.S.R., B.L., B.G., F.-Y.L., H.W., J.E.D., M.L., Q.Q., T.A.M., T.I.M.).
Terence I. Moy
Morphic Therapeutic, Inc, Waltham, MA (M.S.M., M.A., A.S.R., B.L., B.G., F.-Y.L., H.W., J.E.D., M.L., Q.Q., T.A.M., T.I.M.).
François Potus
Steeve Provencher
Olivier Boucherat
Sebastien Bonnet