Distinct functions for Rap1 signaling in vascular morphogenesis and dysfunction

Chrzanowska‐Wodnicka, Magdalena

doi:10.1016/j.yexcr.2013.07.022

Cited by 51 publications

(55 citation statements)

References 95 publications

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“…Rap1 isoforms, as members of the Ras family, are involved in the network of multiple proteins to regulate vascular endothelial cell proliferation, migration and endothelial permeability as well as vascular tone [31]. Rap1b in both smooth muscle and endothelium plays a key role in maintaining blood pressure [32, 33].…”

Section: Discussionmentioning

confidence: 99%

Activation of G protein-coupled estrogen receptor 1 induces coronary artery relaxation via Epac/Rap1-mediated inhibition of RhoA/Rho kinase pathway in parallel with PKA

Zhang

Zhao

et al. 2017

PLoS ONE

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Previously, we reported that cAMP/PKA signaling is involved in GPER-mediated coronary relaxation by activating MLCP via inhibition of RhoA pathway. In the current study, we tested the hypothesis that activation of GPER induces coronary artery relaxation via inhibition of RhoA/Rho kinase pathway by cAMP downstream targets, exchange proteins directly activated by cAMP (Epac) as well as PKA. Our results show that Epac inhibitors, brefeldin A (BFA, 50 μM), or ESI-09 (20 μM), or CE3F4 (100 μM), all partially inhibited porcine coronary artery relaxation response to the selective GPER agonist, G-1 (0.3–3 μM); while concurrent administration of BFA and PKI (5 μM), a PKA inhibitor, almost completely blocked the relaxation effect of G-1. The Epac specific agonist, 8-CPT-2Me-cAMP (007, 1–100 μM), induced a concentration-dependent relaxation response. Furthermore, the activity of Ras-related protein 1 (Rap1) was up regulated by G-1 (1 μM) treatment of porcine coronary artery smooth muscle cells (CASMCs). Phosphorylation of vasodilator-stimulated phosphoprotein (p-VASP) was elevated by G-1 (1 μM) treatment, but not by 007 (50 μM); and the effect of G-1 on p-VASP was blocked by PKI, but not by ESI-09, an Epac antagonist. RhoA activity was similarly down regulated by G-1 and 007, whereas ESI-09 restored most of the reduced RhoA activity by G-1 treatment. Furthermore, G-1 decreased PGF2α-induced p-MYPT1, which was partially reversed with either ESI-09 or PKI; whereas, concurrent administration of ESI-09 and PKI totally prevented the inhibitory effect of G-1. The inhibitory effects of G-1 on p- MLC levels in CASMCs were mostly restored by either ESI-09 or PKI. These results demonstrate that activation of GPER induces coronary artery relaxation via concurrent inhibition of RhoA/Rho kinase by Epac/Rap1 and PKA. GPER could be a potential drug target for preventing and treating cardiovascular diseases.

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Section: Discussionmentioning

confidence: 99%

Activation of G protein-coupled estrogen receptor 1 induces coronary artery relaxation via Epac/Rap1-mediated inhibition of RhoA/Rho kinase pathway in parallel with PKA

Zhang

Zhao

et al. 2017

PLoS ONE

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“…Subsequently, Wang and colleagues described the crystal structures of zebrafish Plexin C1 cytoplasmic region in complex with Rap1, thus unveiling the conformational changes and molecular details that allow Rap1-binding by plexins 13 . It is well known that Rap1-GTP effectively controls vascular morphogenesis 76 and promotes, via talin, the conformational activation of integrins and the ensuing adhesion of different cell types to the extracellular matrix 76,77 (Fig. 1).…”

Section: Sema3ementioning

confidence: 99%

Class 3 semaphorins in cardiovascular development

Valdembri

Regano

Maione

et al. 2016

Cell Adhesion & Migration

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Secreted class 3 semaphorins (Sema3), which signal through holoreceptor complexes that are formed by different subunits, such as neuropilins (Nrps), proteoglycans, and plexins, were initially characterized as fundamental regulators of axon guidance during embryogenesis. Subsequently, Sema3A, Sema3C, Sema3D, and Sema3E were discovered to play crucial roles in cardiovascular development, mainly acting through Nrp1 and Plexin D1, which funnels the signal of multiple Sema3 in vascular endothelial cells. Mechanistically, Sema3 proteins control cardiovascular patterning through the enzymatic GTPase-activating-protein activity of the cytodomain of Plexin D1, which negatively regulates the function of Rap1, a small GTPase that is well-known for its ability to drive vascular morphogenesis and to elicit the conformational activation of integrin adhesion receptors.

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“…43 The primary data describing any embryonic phenotypes of these animals, as well as the EC-specific double homozygous knockout of Rap1a and Rap1b have not yet been published. 43,44 These experiments would shed light on potential redundancies and unique functions of Rap1a and Rap1b in the endothelium.…”

Section: Rap1 As a Central Mediator Of Endothelial Cell-cell And Cellmentioning

confidence: 99%

Regulation of vascular endothelial junction stability and remodeling through Rap1-Rasip1 signaling

Wilson

2014

Cell Adhesion & Migration

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Distinct functions for Rap1 signaling in vascular morphogenesis and dysfunction

Cited by 51 publications

References 95 publications

Activation of G protein-coupled estrogen receptor 1 induces coronary artery relaxation via Epac/Rap1-mediated inhibition of RhoA/Rho kinase pathway in parallel with PKA

Activation of G protein-coupled estrogen receptor 1 induces coronary artery relaxation via Epac/Rap1-mediated inhibition of RhoA/Rho kinase pathway in parallel with PKA

Class 3 semaphorins in cardiovascular development

Regulation of vascular endothelial junction stability and remodeling through Rap1-Rasip1 signaling

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