Vascular Permeability Factor/Vascular Endothelial Cell Growth Factor-mediated Permeability Occurs through Disorganization of Endothelial Junctional Proteins

Abstract

Vascular permeability factor/vascular endothelial growth factor stimulates endothelial proliferation, angiogenesis, and increased vascular permeability in vivo. We investigated mechanisms of vascular permeability factor-mediated endothelial monolayer permeability changes in vitro. [ 14 C]Albumin flux across endothelial monolayers was measured following a 90-min exposure to vascular permeability factor (660 pM). Vascular permeability factor increased albumin flux to 3.4 times that of control albumin flux. Endothelial monolayers were also incubated for 90 min with vascular permeability factor plus Gö 6976 (10 nM), staurosporine (1 M), wortmannin (10 nM), AG126 (1 and 2.67 M), and PD98059 (20 M). Vascular permeability factor-mediated permeability was not blocked by Gö 6976, an antagonist of "classical" protein kinase C, staurosporine, a pan-protein kinase C antagonist, nor wortmannin, a PI3-kinase blocker, but was blocked by incubation with AG126 or PD98059, inhibitors of mitogen-activated protein kinase activation. Immunofluorescent staining of the junctional proteins VE-cadherin and occludin showed a loss of these proteins from the endothelial junction that was prevented by co-incubation with AG126 or PD98059. These data demonstrate that vascular permeability factor increases albumin permeability across endothelial monolayers in vitro and suggests that permeability increases through rearrangement of endothelial junctional proteins involving the mitogen-activated protein kinase signal transduction pathway.

Vascular endothelial cadherin and �-catenin in human fetoplacental vessels of pregnancies complicated by Type 1 diabetes: associations with angiogenesis and perturbed barrier function

“…9). These observations, in conjunction with those of established studies showing regulation of permeability by adherens junctions in culture [8,14,16] and in retinal, pulmonary, tracheal, placental and coronary microvessels [12,16,17,30,31,32,44,45,46] lead us to hypothesise that adherens junctional perturbation in diabetes contributes largely to the observed vascular leakiness. Electron microscopical studies did not reveal the presence of transendothelial channels, the alternate induced transport pathway [47] for inflamed vessels.…”

“…VEGF has been shown to elicit increased nuclear localisation of β-catenin as well as increased cyclin D1 in the umbilical vein cells, which correlated with increased proliferation [14]. Moreover, VEGF-induced tyrosine phosphorylation of VE-cadherin and β-catenin leads to junctional alterations and increased permeability to macromolecules [15,16]. Perturbation of the junctional molecules may be a complication of diabetes mellitus with resultant leaky angiogenic vessels.…”

C1q as a unique player in angiogenesis with therapeutic implication in wound healing

“…C1q exhibits all of the features of an angiogenic factor inasmuch as it induces an increase in vascular leakage as a result of loosening of interendothelial cell junctions and stimulates cell proliferation and migration. The increase in EC permeability induced by C1q and VEGF (23) allows the extravasation of plasma proteins and formation of extracellular matrix favorable to endothelial and stromal cell migration (24). C1q also shares with VEGF the ability to induce the formation of vascular structure evaluated using both the in vitro Matrigel assay and the ex vivo aortic ring assay.…”

Iron supplement prevents lead-induced disruption of the blood–brain barrier during rat development

“…Since the tight junctional protein occludin is closely involved in maintaining endothelial barriers (Kevil et al, 1998a(Kevil et al, , 1998bTrocha et al, 1999), alteration of this protein may lead to the opening of inter-endothelial tight junctions. By Western blot analyses, we have clearly shown a decreased expression of occludin in brain areas examined.…”