Ligand-Independent Activation of Vascular Endothelial Growth Factor Receptor 2 by Fluid Shear Stress Regulates Activation of Endothelial Nitric Oxide Synthase

Jin, Zhigang; Ueba, Hiroto; Tanimoto, Tatsuo; Lungu, Andreea O.; Frame, Mary D.; Berk, Bradford C.

doi:10.1161/01.res.0000089257.94002.96

Cited by 352 publications

(319 citation statements)

References 52 publications

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“…Considerable data suggest that increased force/shear stress on PECAM‐1 leads to Src kinase activation (Chiu et al , 2008) and phosphorylation and ligand independent activation of VEGFR2 and VEGFR3. Activated VEGFR2 and VEGFR3 can trigger several pathways that lead to the activation of integrins and subsequent downstream signalling, including the release of vasoactive signals and vessel dilation (Jin et al , 2003; Fleming et al , 2005). Shear detection requires cell anchorage to the underlying ECM, the nature of which appears to influence the response of the endothelium, since endothelial cells bound to fibronectin versus collagen type I lead to stronger adhesion, manifested as larger and more complex focal adhesions and stronger tension development on PECAM‐1 (Collins et al , 2014).…”

Section: Introductionmentioning

confidence: 99%

Endothelial basement membrane laminin 511 is essential for shear stress response

Russo¹,

Luik²,

Yousif³

et al. 2016

The EMBO Journal

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Shear detection and mechanotransduction by arterial endothelium requires junctional complexes containing PECAM‐1 and VE‐cadherin, as well as firm anchorage to the underlying basement membrane. While considerable information is available for junctional complexes in these processes, gained largely from in vitro studies, little is known about the contribution of the endothelial basement membrane. Using resistance artery explants, we show that the integral endothelial basement membrane component, laminin 511 (laminin α5), is central to shear detection and mechanotransduction and its elimination at this site results in ablation of dilation in response to increased shear stress. Loss of endothelial laminin 511 correlates with reduced cortical stiffness of arterial endothelium in vivo, smaller integrin β1‐positive/vinculin‐positive focal adhesions, and reduced junctional association of actin–myosin II. In vitro assays reveal that β1 integrin‐mediated interaction with laminin 511 results in high strengths of adhesion, which promotes p120 catenin association with VE‐cadherin, stabilizing it at cell junctions and increasing cell–cell adhesion strength. This highlights the importance of endothelial laminin 511 in shear response in the physiologically relevant context of resistance arteries.

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Section: Introductionmentioning

confidence: 99%

Endothelial basement membrane laminin 511 is essential for shear stress response

Russo¹,

Luik²,

Yousif³

et al. 2016

The EMBO Journal

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“…Previously, it was shown that shear stress activated VEGFR2 via conformational change in a ligand-independent manner [24]. The present work indicates that stretch may activate VEGFR2 through similar mechanism based on the following lines of evidence: (1) the VEGF-neutralizing antibody did not affect stretch-induced VEGFR2 phosphorylation ( Figure 3C); (2) the VEGF-neutralizing antibody failed to block stretch-induced WPB exocytosis and leukocyte adhesion in cultured ECs ( Figure 3E Figure S3); (3) mechanical stretch activated VEGFR2 that was exogenously expressed in 293A cells and its downstream signaling pathways (Supplementary information, Figure S4), similar to the case of the activation of angiotensin II type 1 receptor by stretch [25].…”

Section: Discussionmentioning

confidence: 99%

Hypertensive stretch regulates endothelial exocytosis of Weibel-Palade bodies through VEGF receptor 2 signaling pathways

Xiong

Han

et al. 2013

Cell Res

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Regulated endothelial exocytosis of Weibel-Palade bodies (WPBs), the first stage in leukocyte trafficking, plays a pivotal role in inflammation and injury. Acute mechanical stretch has been closely associated with vascular inflammation, although the precise mechanism is unknown. Here, we show that hypertensive stretch regulates the exocytosis of WPBs of endothelial cells (ECs) through VEGF receptor 2 (VEGFR2) signaling pathways. Stretch triggers a rapid release (within minutes) of von Willebrand factor and interleukin-8 from WPBs in cultured human ECs, promoting the interaction between leukocytes and ECs through the translocation of P-selectin to the cell membrane. We further show that hypertensive stretch significantly induces P-selectin translocation of intact ECs and enhances leukocyte adhesion both ex vivo and in vivo. Stretch-induced endothelial exocytosis is mediated via a VEGFR2/PLCγ1/calcium pathway. Interestingly, stretch also induces a negative feedback via a VEGFR2/Akt/nitric oxide pathway. Such dual effects are confirmed using pharmacological and genetic approaches in carotid artery segments, as well as in acute hypertensive mouse models. These studies reveal mechanical stretch as a potent agonist for endothelial exocytosis, which is modulated by VEGFR2 signaling. Thus, VEGFR2 signaling pathways may represent novel therapeutic targets in limiting hypertensive stretch-related inflammation.

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“…In general, PI3-kinase is activated by translocation to the plasma membrane after phosphorylation of transmembrane tyrosine kinase receptors and subsequent interaction of PI3-kinase SH2 domains with phosphotyrosine residues in the receptors (51). It has recently been shown that flow activates PI3-kinase by inducing Src kinase activation and subsequent ligand-independent activation of tyrosine kinase receptors such as the VEGF and purinergic P 2 receptors (26,45). Given that c-Src is expressed in the THAL (28), it is tempting to speculate that flow-dependent activation of c-Src mediates PI3-kinase activation and eNOS trafficking in the THAL.…”

Section: Discussionmentioning

confidence: 99%

Luminal flow induces eNOS activation and translocation in the rat thick ascending limb. II. Role of PI3-kinase and Hsp90

Ortíz¹,

Hong²,

Garvin³

2004

American Journal of Physiology-Renal Physiology

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Endothelial nitric oxide synthase (eNOS) regulates NaCl absorption by the thick ascending limb of the loop of Henle (THAL). We found that augmenting luminal flow induces eNOS activation and translocation to the apical membrane of THALs (Ortiz PA, Hong NJ, and Garvin JL. Am J Physiol Renal Physiol 287: F274 -F280, 2004). In other cells, eNOS activation by shear stress is mediated by phosphatidylinositol 3-OH kinase (PI3)-kinase. We hypothesized that luminal flow induces eNOS activation via PI3-kinase. Pretreatment of THALs with wortmannin, a PI3-kinase inhibitor, significantly reduced flow-induced nitric oxide (NO) release by 75% (from 53.6 Ϯ 6 to 13.2 Ϯ 5.7 pA/mm). Increasing luminal flow from 0 to 20 nl/min induced eNOS translocation to the apical membrane, whereas in the presence of wortmannin eNOS translocation was prevented (basolateral ϭ 32 Ϯ 2%, middle ϭ 38 Ϯ 1%, apical ϭ 30 Ϯ 1%, n ϭ 5, not significant vs. no flow). We next studied which PI3-kinase product mediates eNOS translocation. Addition of PI(3,4,5)P 3 (5 M) in the absence of flow increased NO levels (P Ͻ 0.05) and induced eNOS translocation to the apical membrane (from 40 Ϯ 4 to 60 Ϯ 2% of total eNOS, n ϭ 6, P Ͻ 0.05). Incubation with PI(3,4)P 2 or PI(4,5)P2 did not change eNOS localization. We next tested whether heat shock protein (Hsp)90 is involved in eNOS translocation. The Hsp90 inhibitor geldanamycin blocked flow-induced eNOS translocation to the apical membrane (n ϭ 6). Flow also induced translocation of Hsp90 to the apical membrane (from 35 Ϯ 2 to 57 Ϯ 2%; P Ͻ 0.05) in a PI3-kinasedependent manner. We conclude that luminal flow induces eNOS translocation and activation in the THAL via PI3-kinase and that Hsp90 is involved in eNOS translocation to the apical membrane. nitric oxide; renal tubules; trafficking; phosphatidylinositol; heat shock protein; endothelial nitric oxide synthase IN POLARIZED EPITHELIAL CELLS of the kidney, respiratory tract, and testis, nitric oxide (NO) produced by endothelial NO synthase (eNOS) regulates important cellular functions (14,27,29,34,55,57,60). Thus eNOS activity and NO production must be tightly regulated in these cells. We previously reported that NO acts as an autacoid to inhibit NaCl and bicarbonate absorption by the thick ascending limb of the loop of Henle (THAL) (31,32,39). More recently, we identified eNOS as the NOS isoform responsible for the regulation of NaCl absorption by the THAL (35, 38). We recently observed that increasing luminal flow acutely stimulated eNOS activity and induced translocation of eNOS from the basolateral membrane and cytoplasm to the apical membrane of isolated THALs (34a). However, the signaling cascade that mediates eNOS activation and translocation by flow is unknown.Regulation of eNOS has been studied in depth in vascular endothelial cells, where one of the most potent activators of eNOS is flow-induced shear stress (5, 46). The mechanism by which flow activates eNOS in these cells is independent of changes in intracellular calcium and involves activation of the pho...

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Ligand-Independent Activation of Vascular Endothelial Growth Factor Receptor 2 by Fluid Shear Stress Regulates Activation of Endothelial Nitric Oxide Synthase

Cited by 352 publications

References 52 publications

Endothelial basement membrane laminin 511 is essential for shear stress response

Endothelial basement membrane laminin 511 is essential for shear stress response

Hypertensive stretch regulates endothelial exocytosis of Weibel-Palade bodies through VEGF receptor 2 signaling pathways

Luminal flow induces eNOS activation and translocation in the rat thick ascending limb. II. Role of PI3-kinase and Hsp90

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