Novel approaches to pulmonary arterial hypertension drug discovery

Sung, Yon K.; Yuan, Ke; Perez, Vinicio A. de Jesus

doi:10.1517/17460441.2016.1153625

Cited by 7 publications

(6 citation statements)

References 77 publications

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“…We are entering an exciting era for new therapeutics in the treatment of PAH (69). Gene expression studies and highthroughput studies have emerged as powerful tools to identify novel therapeutic targets and biologically active compounds able to modulate dedicated pathways in PAH.…”

Section: Confirmatory Investigationsmentioning

confidence: 99%

Translating Research into Improved Patient Care in Pulmonary Arterial Hypertension

Bonnet

Provencher

Guignabert

et al. 2017

Am J Respir Crit Care Med

118

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Section: Confirmatory Investigationsmentioning

confidence: 99%

Translating Research into Improved Patient Care in Pulmonary Arterial Hypertension

Bonnet

Provencher

Guignabert

et al. 2017

Am J Respir Crit Care Med

118

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“…Importantly, the rescue of BMPRII expression may not exclusively benefit PAH patients but also patients suffering from pancreatic and lung fibrosis where BMPRII deficiency has been implicated [ 43 , 44 ]. BMPRII restoration can be targeted at different levels: genetic-based therapies, transcriptional and translational regulation, protein activity, and processing as well as SMAD downstream signaling modulation [ 27 , 75 , 76 ] (Fig. 3 ).…”

Section: Restoring Bmprii Signaling As a Therapeutic Strategymentioning

confidence: 99%

BMP type II receptor as a therapeutic target in pulmonary arterial hypertension

Orriols

Gomez‐Puerto

Dijke

2017

Cell. Mol. Life Sci.

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Pulmonary arterial hypertension (PAH) is a chronic disease characterized by a progressive elevation in mean pulmonary arterial pressure. This occurs due to abnormal remodeling of small peripheral lung vasculature resulting in progressive occlusion of the artery lumen that eventually causes right heart failure and death. The most common cause of PAH is inactivating mutations in the gene encoding a bone morphogenetic protein type II receptor (BMPRII). Current therapeutic options for PAH are limited and focused mainly on reversal of pulmonary vasoconstriction and proliferation of vascular cells. Although these treatments can relieve disease symptoms, PAH remains a progressive lethal disease. Emerging data suggest that restoration of BMPRII signaling in PAH is a promising alternative that could prevent and reverse pulmonary vascular remodeling. Here we will focus on recent advances in rescuing BMPRII expression, function or signaling to prevent and reverse pulmonary vascular remodeling in PAH and its feasibility for clinical translation. Furthermore, we summarize the role of described miRNAs that directly target the BMPR2 gene in blood vessels. We discuss the therapeutic potential and the limitations of promising new approaches to restore BMPRII signaling in PAH patients. Different mutations in BMPR2 and environmental/genetic factors make PAH a heterogeneous disease and it is thus likely that the best approach will be patient-tailored therapies.

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“…In the past 20 years, the protective roles of BMPR2 on pulmonary vascular have been well studied. Recent studies indicate that manipulation of BMPR2 at different levels including genetic therapies, translational regulation, protein delivery and modulation downstream signalling represents a promising approach to restore normal vascular function [159][160][161] .…”

Section: The Role Of Bmp Signalling In Pulmonary Arterial Hypertensionmentioning

confidence: 99%

BMP9 and BMP10 Act Directly on Vascular Smooth Muscle Cells for Generation and Maintenance of the Contractile State

Wang¹,

Rice²,

Swist³

et al. 2021

Circulation

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Background: Vascular smooth muscle cells (VSMCs) show a remarkable phenotypic plasticity allowing acquisition of contractile or synthetic states but critical information is missing about the physiological signals, promoting formation and maintenance of contractile VSMCs in vivo . BMP9 and BMP10 are known to regulate endothelial quiescence after secretion from the liver and right atrium, whereas a direct role in the regulation of VSMCs was not investigated. Here, we studied the role of BMP9 and BMP10 for controlling formation of contractile VSMCs. Methods: We generated several cell type-specific loss- and gain-of-function transgenic mouse models to investigate the physiological role of BMP9, BMP10, ALK1 and SMAD7 in vivo . Morphometric assessments, expression analysis, blood pressure measurements, single molecule fluorescence in situ hybridization (FISH) were performed together with analysis of isolated pulmonary VSMCs to unravel phenotypic and transcriptomic changes in response to absence or presence of BMP9 and BMP10. Results: Concomitant genetic inactivation of Bmp9 in the germ line and Bmp10 in the right atrium led to dramatic changes in vascular tone and diminution of the VSMC layer with attenuated contractility and decreased systemic as well as right ventricular systolic pressure (RVSP). Vice versa , overexpression of Bmp10 in endothelial cells (ECs) of adult mice dramatically enhanced formation of contractile VSMCs and increased systemic blood pressure as well as RVSP. Likewise, BMP9/10 treatment induced an ALK1-dependent phenotypic switch from synthetic to contractile in pulmonary VSMCs. SMC specific overexpression of Smad7 completely suppressed differentiation and proliferation of VSMCs and reiterated defects observed in adult Bmp9/10 double mutants. Deletion of Alk1 in VSMCs recapitulated the Bmp9/10 phenotype in pulmonary but not in aortic and coronary arteries. Bulk expression analysis and single molecule RNA-FISH uncovered vessel bed-specific, heterogeneous expression of BMP type 1 receptors, explaining phenotypic differences in different Alk1 mutant vessel beds. Conclusions: Our study demonstrates that BMP9 and BMP10 act directly on VSMCs for induction and maintenance of their contractile state. Surprisingly, the effects of BMP9/10 in VSMCs are mediated by different combinations of BMP type 1 receptors in a vessel bed specific manner, offering new opportunities to manipulate blood pressure in the pulmonary circulation.

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Novel approaches to pulmonary arterial hypertension drug discovery

Cited by 7 publications

References 77 publications

Translating Research into Improved Patient Care in Pulmonary Arterial Hypertension

Translating Research into Improved Patient Care in Pulmonary Arterial Hypertension

BMP type II receptor as a therapeutic target in pulmonary arterial hypertension

BMP9 and BMP10 Act Directly on Vascular Smooth Muscle Cells for Generation and Maintenance of the Contractile State

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