Rap1 promotes endothelial mechanosensing complex formation,
            <scp>NO</scp>
            release and normal endothelial function

Lakshmikanthan, Sribalaji; Zheng, Xiaodong; Nishijima, Yoshinori; Sobczak, Magdalena; Szabó, Anikó; Vásquez‐Vivar, Jeannette; Zhang, David X.; Chrzanowska‐Wodnicka, Magdalena

doi:10.15252/embr.201439846

Cited by 45 publications

(77 citation statements)

References 54 publications

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“…Until now, it is unclear whether phosphorylation of VE-cadherin is actively involved in flow-induced mechanotransduction. Of interest, the small GTPase Rap1, which is strongly implicated in endothelial cell–cell junction stabilization and barrier formation [69], is required for functioning of the PECAM-1/VE-cadherin/VEGFR complex in flow sensing [70]. This adds another signaling route to this mechanotransduction pathway.…”

Section: Flow Mechanosensing: Roles Of Pecam-1 and Ve-cadherinmentioning

confidence: 99%

Cell–cell junctional mechanotransduction in endothelial remodeling

Dorland

Huveneers

2016

Cell. Mol. Life Sci.

150

142

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The vasculature is one of the most dynamic tissues that encounter numerous mechanical cues derived from pulsatile blood flow, blood pressure, activity of smooth muscle cells in the vessel wall, and transmigration of immune cells. The inner layer of blood and lymphatic vessels is covered by the endothelium, a monolayer of cells which separates blood from tissue, an important function that it fulfills even under the dynamic circumstances of the vascular microenvironment. In addition, remodeling of the endothelial barrier during angiogenesis and trafficking of immune cells is achieved by specific modulation of cell–cell adhesion structures between the endothelial cells. In recent years, there have been many new discoveries in the field of cellular mechanotransduction which controls the formation and destabilization of the vascular barrier. Force-induced adaptation at endothelial cell–cell adhesion structures is a crucial node in these processes that challenge the vascular barrier. One of the key examples of a force-induced molecular event is the recruitment of vinculin to the VE-cadherin complex upon pulling forces at cell–cell junctions. Here, we highlight recent advances in the current understanding of mechanotransduction responses at, and derived from, endothelial cell–cell junctions. We further discuss their importance for vascular barrier function and remodeling in development, inflammation, and vascular disease.

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Section: Flow Mechanosensing: Roles Of Pecam-1 and Ve-cadherinmentioning

confidence: 99%

Cell–cell junctional mechanotransduction in endothelial remodeling

Dorland

Huveneers

2016

Cell. Mol. Life Sci.

150

142

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“…Uncoupling this pathway through endothelial-specific deletion of P2Y2 or Gq/11 in mice blunts flow-induced vasodilation and elevates blood pressure. Similarly, endothelial-specific deletion of the small GTPase Rap1 blunts flow-induced NO production and enhances blood pressure in mouse models as well [52]. While this response is postulated to be due to Rap1’s influence on endothelial adherens junction structure [52], PECAM-1 knockout mice do not show increased blood pressure [53].…”

Section: The Arterial Microenvironmental and Endothelial Activationmentioning

confidence: 99%

“…Similarly, endothelial-specific deletion of the small GTPase Rap1 blunts flow-induced NO production and enhances blood pressure in mouse models as well [52]. While this response is postulated to be due to Rap1’s influence on endothelial adherens junction structure [52], PECAM-1 knockout mice do not show increased blood pressure [53]. Like Akt, activation of protein kinase A (PKA) also appears to contribute to flow-induced eNOS activation through Ser phosphorylation [47, 54].…”

Section: The Arterial Microenvironmental and Endothelial Activationmentioning

confidence: 99%

The arterial microenvironment: the where and why of atherosclerosis

Yurdagul

Finney

Woolard

et al. 2016

Biochemical Journal

155

112

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The formation of atherosclerotic plaques in the large and medium sized arteries is classically driven by systemic factors, such as elevated cholesterol and blood pressure. However, work over the past several decades has established that atherosclerotic plaque development involves a complex coordination of both systemic and local cues that ultimately determine where plaques form and how plaques progress. While current therapeutics for atherosclerotic cardiovascular disease primarily target the systemic risk factors, a large array of studies suggest that the local microenvironment, including arterial mechanics, matrix remodeling, and lipid deposition, plays a vital role in regulating the local susceptibility to plaque development through the regulation of vascular cell function. Additionally, these microenvironmental stimuli are capable of tuning other aspects of the microenvironment through collective adaptation. In this review, we will discuss the components of the arterial microenvironment, how these components crosstalk to shape the local microenvironment, and the effect of microenvironmental stimuli on vascular cell function during atherosclerotic plaque formation.

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“…Interestingly, mice with one Rap1a allele (EC-Rap1a +/− Rap1b −/− ) exhibited embryonic hemorrhage and significantly reduced viability at weaning, a phenotype absent in mice with one remaining Rap1b allele (EC-Rap1a −/− Rap1b +/− ), signifying relative importance of the Rap1b isoform for normal vessel formation. Remarkably, post-development, deletion of both Rap1 isoforms does not have a deleterious effect on vessel permeability or gross vessel and cell-cell junction morphology (8). Therefore, Rap1 is not absolutely required for maintenance of existing cell-cell junctions and preservation of EB.…”

Section: Introductionmentioning

confidence: 99%

“…Our recent analysis of tissue-specific knockout mice revealed that, via separate mechanisms in smooth muscle and endothelium, Rap1 controls vascular tone and is required for maintenance of normal blood pressure (8, 30). We found that total Rap1b-deficiency leads to hypertension and pathological cardiac hypertrophy.…”

Section: Introductionmentioning

confidence: 99%

Rap1 in endothelial biology

Chrzanowska‐Wodnicka

2017

Current Opinion in Hematology

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Purpose of review Ubiquitously-expressed small GTPase Rap1 is a key modulator of integrin- and cadherin-regulated processes. In endothelium Rap1 promotes angiogenesis and endothelial barrier (EB) function, acting downstream from cAMP-activated Rap1GEF, Epac. Recent in vivo studies in mouse models have provided more information about the physiological role of Rap1 in vessel development and after birth under normal and pathologic conditions. Important molecular details of dynamic regulation of EB are uncovered. Recent findings Rap1 is not essential for initial vessel formation but is critical for vessel stabilization, as double knockout of the two Rap1 isoforms leads to hemorrhage and embryonic lethality. After development, Rap1 is not required for EB maintenance but is critical for NO production and endothelial function. Radil and Afadin mediate Rap1 effects on EB function by regulating connection with Rho GTPases, actomyosin cytoskeleton and cell-cell adhesion receptors. Summary Rap1 is critically required for NO release and normal endothelial function in vivo. Mechanistic studies lead to a novel paradigm of Rap1 as a critical regulator of EC shear stress responses and endothelial homeostasis. Increased understanding of molecular mechanisms underlying EB regulation may identify novel pharmacological targets for retinopathies and conditions with altered EB function or when increased EB is desired.

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Rap1 promotes endothelial mechanosensing complex formation, NO release and normal endothelial function

Cited by 45 publications

References 54 publications

Cell–cell junctional mechanotransduction in endothelial remodeling

Cell–cell junctional mechanotransduction in endothelial remodeling

The arterial microenvironment: the where and why of atherosclerosis

Rap1 in endothelial biology

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