Pathophysiological consequences of VEGF-induced vascular permeability

Weis, Sara M.; Cheresh, David A.

doi:10.1038/nature03987

Cited by 793 publications

(660 citation statements)

References 90 publications

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“…While our previous studies show that VEGF-mediated VP depends on Src, VEGF can also use other proteins such as PI3K␥/␦ to induce VP through tyrosine phosphorylation of VE-cadherin and disruption of adherens junctions. 18,33 Our results suggest that, in the presence of Sema3A, VEGF uses these alternative pathways. Importantly, these findings also indicate that Sema3A and VEGF induce VP through distinct pathways.…”

Section: Discussionmentioning

confidence: 76%

Semaphorin 3A suppresses VEGF-mediated angiogenesis yet acts as a vascular permeability factor

Acevedo

Barillas

Weis

et al. 2008

Blood

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193

213

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Semaphorin 3A (Sema3A), a known inhibitor of axonal sprouting, also alters vascular patterning. Here we show that Sema3A selectively interferes with VEGF-but not bFGF-induced angiogenesis in vivo. Consistent with this, Sema3A disrupted VEGFbut not bFGF-mediated endothelial cell signaling to FAK and Src, key mediators of integrin and growth factor signaling; however, signaling to ERK by either growth factor was unperturbed. Since VEGF is also a vascular permeability (VP) factor, we examined the role of Sema3A on VEGF-mediated VP in mice. Surprisingly, Sema3A not only stimulated VEGF-mediated VP but also potently induced VP in the absence of VEGF. Sema3A-mediated VP was inhibited either in adult mice expressing a conditional deletion of endothelial neuropilin-1 (Nrp-1) or in wild-type mice systemically treated with a functionblocking Nrp-1 antibody. While both Sema3A-and VEGF-induced VP was Nrp-1 dependent, they use distinct downstream effectors since VEGF-but not Sema3A-induced VP required Src kinase signaling. These findings define a novel role for Sema3A both as a selective inhibitor of VEGF-mediated angiogenesis and a potent inducer of VP.

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Section: Discussionmentioning

confidence: 76%

Semaphorin 3A suppresses VEGF-mediated angiogenesis yet acts as a vascular permeability factor

Acevedo

Barillas

Weis

et al. 2008

Blood

Self Cite

193

213

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“…In this regard, electron microscopy unveils that the barrier integrity is dramatically altered in KS with prominent inflammatory cell infiltrates. Release of blood components into the surrounding tissue is associated with edema formation, thickness of the perivascular compartment and local inflammatory processes that in turn exacerbate the leaky phenotype (Weis and Cheresh, 2005). These processes potentially trigger endothelial activation and vascular permeability, which are involved in the angioproliferative KS phenotype.…”

Section: Discussionmentioning

confidence: 99%

Remodeling of VE-cadherin junctions by the human herpes virus 8 G-protein coupled receptor

et al. 2010

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Kaposi Sarcoma (KS) are opportunistic tumors, associated with human herpes virus 8 (HHV8) infection. KS development is highly favored by immune-depression and remains the second most frequent tumor in acquired immune deficiency syndrome patients. Although it has been shown that experimental expression of the HHV8 G-proteincoupled receptor (vGPCR) in the endothelial compartment is alone sufficient to recapitulate the formation and progression of KS-like lesions, its functional effects on endothelial homeostasis are not fully understood. Here we show that vGPCR expression in endothelial cells induces an increase in paracellular permeability both in vivo and in vitro. By using pharmacological inhibitors and small interference RNA-based knockdown, we demonstrate an essential role for the PI(3)Kinase-c/Rac nexus in vGPCRmediated permeability. This was further accompanied by dramatic remodeling of VE-cadherin-dependent cell-cell junctions. Importantly, this in vitro vGPCR-initiated signaling signature was observed in a large panel of human KS. Altogether, our results support the hypothesis that endothelial vGPCR signaling is co-opted in KS, and unveil new key cellular targets for therapeutic intervention.

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“…Increase of vascular permeability results in enhanced movements of fluids and solutes (39), as well as inflammatory mediators, from the intravascular into the interstitial and/or intracellular compartment, leading to change of cellular and extracellular osmolarity, disturbance of cell membrane conductivity, cell swelling, and interstitial edema (38), thereby compromising myocardial contractile function and potentially leading to lethal arrhythmias (12,38). Inflammatory mediators such as TNF-␣, free oxygen radicals, and interleukins have been shown to play a major role in contractile dysfunction in the microembolized myocardium following coronary microembolization (15,17,34), possibly indicating the role of inflammation and/or edema in its pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Relationship between surface area of nonperfused myocardium and extravascular extraction of contrast agent following coronary microembolization

Malyar

Lerman

Gössl

et al. 2011

American Journal of Physiology-Regulatory, Integrative and Comp

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Malyar NM, Lerman LO, Gössl M, Beighley PE, Ritman EL. Relationship between surface area of nonperfused myocardium and extravascular extraction of contrast agent following coronary microembolization. Am J Physiol Regul Integr Comp Physiol 301: R430-R437, 2011. First published May 4, 2011 doi:10.1152/ajpregu.00428.2010.-Myocardial microvascular permeability and coronary sinus concentration of muscle metabolites have been shown to increase after myocardial ischemia due to epicardial coronary artery occlusion and reperfusion. However, their association with coronary microembolization is not well defined. This study tested the hypothesis that acute coronary microembolization increases microvascular permeability in the porcine heart. The left anterior descending perfusion territories of 34 anesthetized pigs (32 Ϯ 3 kg) were embolized with equal volumes of microspheres of one of three diameters (10, 30, or 100 m) and at three different doses for each size. Electron beam computed tomography (EBCT) was used to assess in vivo, microvascular extraction of a nonionic contrast agent (an index of microvascular permeability) before and after microembolization with microspheres at baseline and during adenosine infusion. A high-resolution three-dimensional microcomputed tomography (micro-CT) scanner was subsequently used to obtain ex vivo, the volume and corresponding surface area of the embolized myocardial islands within the perfusion territories of the microembolized coronary artery. EBCT-derived microvascular extraction of contrast agent increased within minutes after coronary microembolization (P Ͻ 0.001 vs. baseline and vs. control values). The increase in coronary microvascular permeability was highly correlated to the micro-CT-derived total surface area of the nonperfused myocardium (r ϭ 0.83, P Ͻ 0.001). In conclusion, myocardial extravascular accumulation of contrast agent is markedly increased after coronary microembolization and its magnitude is in proportion to the surface area of the interface between the nonperfused and perfused territories. microspheres; EBCT; micro-CT; microvascular permeability A BALANCE BETWEEN DELIVERY of vital nutrients and removal of waste products from the myocardium is pivotal for maintaining the physiological contractile function of the myocytes and for the coordinated electrical conductance along the cells' membranes. However, it has been shown that myocardial microvascular permeability can change under various pathologic and metabolic circumstances such as diabetes mellitus (24, 41), hypercholesterolemia (32), hypertension (31), and acute myocardial ischemia followed by reperfusion (29). Embolization of microscopic plaque debris into the distal coronary bed during coronary interventions is a common and frequent event (9, 10, 35) that might be associated with microinfarctions and with adverse clinical outcome (7, 10).We have previously demonstrated that experimental coronary microembolization leads to a decrease in regional myocardial contractility that is proportional to the surface...

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Pathophysiological consequences of VEGF-induced vascular permeability

Cited by 793 publications

References 90 publications

Semaphorin 3A suppresses VEGF-mediated angiogenesis yet acts as a vascular permeability factor

Semaphorin 3A suppresses VEGF-mediated angiogenesis yet acts as a vascular permeability factor

Remodeling of VE-cadherin junctions by the human herpes virus 8 G-protein coupled receptor

Relationship between surface area of nonperfused myocardium and extravascular extraction of contrast agent following coronary microembolization

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