Endothelin-Bone morphogenetic protein type 2 receptor interaction induces pulmonary artery smooth muscle cell hyperplasia in pulmonary arterial hypertension

Maruyama, Hidekazu; Dewachter, Céline; Belhaj, Asmae; Rondelet, Benoît; Sakai, Satoshi; Remmelink, Myriam; Vachiéry, Jean‐Luc; Naeije, Robert; Dewachter, Laurence

doi:10.1016/j.healun.2014.09.011

Cited by 32 publications

(38 citation statements)

References 29 publications

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“…Gremlin 1 is increased in the lung during the development of PH and plays an important pathogenetic role by antagonizing BMP signaling. [8][9][10][11]13,51 Our findings in Grem1 þ/mice confirmed the important BMP-blocking action caused by increased gremlin 1 during the development of HPH (Supplemental Fig. 2).…”

Section: Discussionsupporting

confidence: 77%

Gremlin 1 blocks vascular endothelial growth factor signaling in the pulmonary microvascular endothelium

et al. 2020

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The bone morphogenetic protein (BMP) antagonist gremlin 1 plays a central role in the pathogenesis of hypoxic pulmonary hypertension (HPH). Recently, non-canonical functions of gremlin 1 have been identified, including specific binding to the vascular endothelial growth factor receptor-2 (VEGFR2). We tested the hypothesis that gremlin 1 modulates VEGFR2 signaling in the pulmonary microvascular endothelium. We examined the effect of gremlin 1 haploinsufficiency on the expression of VEGF responsive genes and proteins in the hypoxic (10% O2) murine lung in vivo. Using human microvascular endothelial cells in vitro we examined the effect of gremlin 1 on VEGF signaling. Gremlin 1 haploinsufficiency (Grem1+/–) attenuated the hypoxia-induced increase in gremlin 1 observed in the wild-type mouse lung. Reduced gremlin 1 expression in hypoxic Grem1+/– mice restored VEGFR2 expression and endothelial nitric oxide synthase (eNOS) expression and activity to normoxic values. Recombinant monomeric gremlin 1 inhibited VEGFA-induced VEGFR2 activation, downstream signaling, and VEGF-induced increases in Bcl-2, cell number, and the anti-apoptotic effect of VEGFA in vitro. These results show that the monomeric form of gremlin 1 acts as an antagonist of VEGFR2 activation in the pulmonary microvascular endothelium. Given the previous demonstration that inhibition of VEGFR2 causes marked worsening of HPH, our results suggest that increased gremlin 1 in the hypoxic lung, in addition to blocking BMP receptor type-2 (BMPR2) signaling, contributes importantly to the development of PH by a non-canonical VEGFR2 blocking activity.

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Section: Discussionsupporting

confidence: 77%

Gremlin 1 blocks vascular endothelial growth factor signaling in the pulmonary microvascular endothelium

et al. 2020

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“…Id proteins are major downstream targets of BMP signaling, among which Id1 is a critical downstream effector of BMP signaling in PASMCs [37]. Downregulation of BMPRII protein reduces the expression of Id1 gene, which further promotes PASMC proliferation [37,38]. Recent study has demonstrated that PDGF inhibits BMPRII/ Id1 signaling and thus promotes PASMC proliferation [39].…”

Section: Discussionmentioning

confidence: 99%

SphK1/S1P Mediates PDGF-Induced Pulmonary Arterial Smooth Muscle Cell Proliferation via miR-21/BMPRII/Id1 Signaling Pathway

Wang

Zhu

et al. 2018

Cell Physiol Biochem

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Background/Aims: The underlying molecular mechanisms involved in sphingosine kinase 1 (SphK1)/sphingosine 1-phosphate (S1P) mediation of platelet-derived growth factor (PDGF)-induced pulmonary arterial smooth muscle cell (PASMC) proliferation are still unclear, and the present study aims to address this issue. Methods: Small interfering RNA (siRNA) and microRNA inhibitor transfection was performed to block the expression of SphK1, bone morphogenetic protein receptor II (BMPRII) and microRNA-21 (miR-21). Gene expression levels of SphK1, BMPRII and inhibitor of DNA binding 1 (Id1) were detected by immunoblotting, miR-21 expression level was examined with qRT-PCR, and S1P production was measured by ELISA. Additionally, PASMC proliferation was determined by BrdU incorporation assay. Results: Our results indicated that PDGF increased the expression of SphK1 protein and S1P production, up-regulated miR-21 expression, reduced BMPRII and Id1 expression, and promoted PASMCs proliferation. Pre-silencing of SphK1 with siRNA reversed PDGF-induced S1P production, miR-21 up-regulation, BMPRII and Id1 down-regulation, as well as PASMC proliferation. Pre-inhibition of miR-21 also blocked BMPRII and Id1 down-regulation as well as PASMC proliferation caused by PDGF. Knockdown of BMPRII down-regulated Id1 expression in PASMCs. We further found that inhibition of PI3K/Akt and ERK signaling pathways, particularly ERK cascade, suppressed PDGF-induced above changes. Conclusion: Our study indicates that SphK1/S1P pathway plays an important role in PDGF-induced PASMC proliferation via miR-21/BMPRII/Id1 axis and targeting against SphK1/S1P axis might be a novel strategy in the prevention and treatment of pulmonary arterial hypertension (PAH).

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“…Moreover, migration of PASMCs from PAH patients is associated with increased p38 activation (267). Similar to ECs, downregulation of BMPR2 in PASMCs is associated with upregulation of p38 (157), further solidifying the link between BMPR2 loss of function and p38 activation in PH vascular remodeling.…”

Section: Pathways and Targetsmentioning

confidence: 65%

Update on novel targets and potential treatment avenues in pulmonary hypertension

Huetsch

Suresh

Bernier

et al. 2016

American Journal of Physiology-Lung Cellular and Molecular Phys

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Pulmonary hypertension (PH) is a condition marked by a combination of constriction and remodeling within the pulmonary vasculature. It remains a disease without a cure, as current treatments were developed with a focus on vasodilatory properties but do not reverse the remodeling component. Numerous recent advances have been made in the understanding of cellular processes that drive pathologic remodeling in each layer of the vessel wall as well as the accompanying maladaptive changes in the right ventricle. In particular, the past few years have yielded much improved insight into the pathways that contribute to altered metabolism, mitochondrial function, and reactive oxygen species signaling and how these pathways promote the proproliferative, promigratory, and antiapoptotic phenotype of the vasculature during PH. Additionally, there have been significant advances in numerous other pathways linked to PH pathogenesis, such as sex hormones and perivascular inflammation. Novel insights into cellular pathology have suggested new avenues for the development of both biomarkers and therapies that will hopefully bring us closer to the elusive goal: a therapy leading to reversal of disease.

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Endothelin-Bone morphogenetic protein type 2 receptor interaction induces pulmonary artery smooth muscle cell hyperplasia in pulmonary arterial hypertension

Cited by 32 publications

References 29 publications

Gremlin 1 blocks vascular endothelial growth factor signaling in the pulmonary microvascular endothelium

Gremlin 1 blocks vascular endothelial growth factor signaling in the pulmonary microvascular endothelium

SphK1/S1P Mediates PDGF-Induced Pulmonary Arterial Smooth Muscle Cell Proliferation via miR-21/BMPRII/Id1 Signaling Pathway

Update on novel targets and potential treatment avenues in pulmonary hypertension

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