Activation of Vascular Endothelial Growth Factor (VEGF) Receptor 2 Mediates Endothelial Permeability Caused by Cyclic Stretch

Tian, Yufeng; Gawlak, Grzegorz; O’Donnell, James J.; Birukova, Anna A.; Birukov, Konstantin G.

doi:10.1074/jbc.m115.690487

Cited by 60 publications

(59 citation statements)

References 74 publications

(78 reference statements)

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“…For example, pathological levels of mechanical stretch, as in ventilator induced lung injury [7,57], activate kinase cascades via VE-cadherin and VEGFR2 to induce endothelial junction remodeling [20]. Similar processes might also predict that arterioles in fibrotic lung tissue would be more susceptible to damage by mechanical ventilation.…”

Section: Discussionmentioning

confidence: 99%

“…Fluid shear alignment (flow sensing), for example, involves force transduction complexes at interendothelial junctions that require platelet endothelial cell adhesion molecule one (PECAM-1), vascular endothelial growth factor 2 (VEGFR2), and vascular endothelial cadherin (VE-cadherin) [1,18,19], which is the main adhesion molecule at endothelial junctions. Besides fluid shear stress, other perturbations such as cyclic stretch in the lung appear to activate a similar signaling cascade [20]. In biophysical studies, we showed that directly perturbing VE-cadherin receptors on cell surfaces with VE-cadherin-modified magnetic beads activated similar signals as in flow sensing, but without PECAM-1 [21].…”

Section: Introductionmentioning

confidence: 99%

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Substrate stiffness and VE-cadherin mechano-transduction coordinate to regulate endothelial monolayer integrity

et al. 2017

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The vascular endothelium is subject to diverse mechanical cues that regulate vascular endothelial barrier function. In addition to rigidity sensing through integrin adhesions, mechanical perturbations such as changes in fluid shear stress can also activate force transduction signals at intercellular junctions. This study investigated how extracellular matrix rigidity and intercellular force transduction, activated by vascular endothelial cadherin, coordinate to regulate the integrity of endothelial monolayers. Studies used complementary mechanical measurements of endothelial monolayers grown on patterned substrates of variable stiffness. Specifically perturbing VE-cadherin receptors activated intercellular force transduction signals that increased integrin-dependent cell contractility and disrupted cell-cell and cell-matrix adhesions. Further investigations of the impact of substrate rigidity on force transduction signaling, demonstrated how cells integrate extracellular mechanics cues and intercellular force transduction signals, to regulate endothelial integrity and global tissue mechanics. VE-cadherin specific signaling increased focal adhesion remodeling and cell contractility, while sustaining the overall mechanical equilibrium at the mesoscale. Conversely, increased substrate rigidity exacerbates the disruptive effects of intercellular force transduction, by increasing heterogeneity in monolayer stress distributions. The results provide new insights into how substrate stiffness and intercellular force transduction coordinate to regulate endothelial monolayer integrity.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Substrate stiffness and VE-cadherin mechano-transduction coordinate to regulate endothelial monolayer integrity

et al. 2017

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“…In fact even inapparent cellular stresses like breathing-directed cyclic stretching of the pulmonary endothelium (88, 89) may contribute to capillary leakage when uncoupled from normal MEC integrity. The cause of vascular leakage during hantavirus diseases has been speculated to stem from a wide range of effectors, including growth factors, kinins, immune responses, cytokines, T cells, and permeability factors (18–20, 29, 31, 32, 35, 36, 39, 77, 90).…”

Section: Discussionmentioning

confidence: 99%

The Andes Virus Nucleocapsid Protein Directs Basal Endothelial Cell Permeability by Activating RhoA

Gorbunova

Simons

Gavrilovskaya

et al. 2016

mBio

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Andes virus (ANDV) predominantly infects microvascular endothelial cells (MECs) and nonlytically causes an acute pulmonary edema termed hantavirus pulmonary syndrome (HPS). In HPS patients, virtually every pulmonary MEC is infected, MECs are enlarged, and infection results in vascular leakage and highly lethal pulmonary edema. We observed that MECs infected with the ANDV hantavirus or expressing the ANDV nucleocapsid (N) protein showed increased size and permeability by activating the Rheb and RhoA GTPases. Expression of ANDV N in MECs increased cell size by preventing tuberous sclerosis complex (TSC) repression of Rheb-mTOR-pS6K. N selectively bound the TSC2 N terminus (1 to 1403) within a complex containing TSC2/TSC1/TBC1D7, and endogenous TSC2 reciprocally coprecipitated N protein from ANDV-infected MECs. TSCs normally restrict RhoA-induced MEC permeability, and we found that ANDV infection or N protein expression constitutively activated RhoA. This suggests that the ANDV N protein alone is sufficient to activate signaling pathways that control MEC size and permeability. Further, RhoA small interfering RNA, dominant-negative RhoA(N19), and the RhoA/Rho kinase inhibitors fasudil and Y27632 dramatically reduced the permeability of ANDV-infected MECs by 80 to 90%. Fasudil also reduced the bradykinin-directed permeability of ANDV and Hantaan virus-infected MECs to control levels. These findings demonstrate that ANDV activation of RhoA causes MEC permeability and reveal a potential edemagenic mechanism for ANDV to constitutively inhibit the basal barrier integrity of infected MECs. The central importance of RhoA activation in MEC permeability further suggests therapeutically targeting RhoA, TSCs, and Rac1 as potential means of resolving capillary leakage during hantavirus infections.

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“…Afadin is necessary for maintaining tissue integrity and barrier function under high tension and is particularly important for maintaining adhesion at tricellular junctions (Choi et al, 2016; Tian et al, 2016). The Drosophila Afadin ortholog, Canoe, is critical for linking the actin cytoskeleton to the AJ during the mechanical stresses of development (Choi et al, 2011; Sawyer et al, 2011).…”

Section: Scaffold Proteins Regulate Rho Gtpase Output At Cell-cell Jumentioning

confidence: 99%

Rho GTPases and actomyosin: Partners in regulating epithelial cell-cell junction structure and function

Arnold

Stephenson

Miller

2017

Experimental Cell Research

121

118

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Epithelial tissues are defined by polarized epithelial cells that are integrated into tissues and exhibit barrier function in order to regulate what is allowed to pass between cells. Cell-cell junctions must be stable enough to promote barrier function and tissue integrity, yet plastic enough to remodel when necessary. This remarkable ability to dynamically sense and respond to changes in cell shape and tissue tension allows cell-cell junctions to remain functional during events that disrupt epithelial homeostasis including morphogenesis, wound healing, and cell division. In order to achieve this plasticity, both tight junctions and adherens junctions are coupled to the underlying actomyosin cytoskeleton. Here, we discuss the importance of the junctional linkage to actomyosin and how a localized zone of active RhoA along with other Rho GTPases work together to orchestrate junctional actomyosin dynamics. We focus on how scaffold proteins help coordinate Rho GTPases, their upstream regulators, and their downstream effectors for efficient, localized Rho GTPase signaling output. Additionally, we highlight important roles junctional actin-binding proteins play in addition to their traditional roles in organizing actin. Together, Rho GTPases, their regulators, and effectors form compartmentalized signaling modules that regulate actomyosin structure and contractility to achieve proper cell-cell adhesion and tissue barriers.

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Activation of Vascular Endothelial Growth Factor (VEGF) Receptor 2 Mediates Endothelial Permeability Caused by Cyclic Stretch

Cited by 60 publications

References 74 publications

Substrate stiffness and VE-cadherin mechano-transduction coordinate to regulate endothelial monolayer integrity

Substrate stiffness and VE-cadherin mechano-transduction coordinate to regulate endothelial monolayer integrity

The Andes Virus Nucleocapsid Protein Directs Basal Endothelial Cell Permeability by Activating RhoA

Rho GTPases and actomyosin: Partners in regulating epithelial cell-cell junction structure and function

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