Deciphering Vascular Endothelial Cell Growth Factor/Vascular Permeability Factor Signaling to Vascular Permeability

Vascular endothelial cell growth factor (VEGF) was originally described as a potent vascular permeability factor (VPF) that importantly contributes to vascular pathobiology. The signaling pathways that underlie VEGF/VPF-induced permeability are not well defined. Furthermore, endogenous vascular peptides that regulate this important VPF function are currently unknown. We report here that VPF significantly enhances permeability in aortic endothelial cells via a linked signaling pathway, sequentially involving Src, ERK, JNK, and phosphatidylinositol 3-kinase/AKT. This leads to the serine/threonine phosphorylation and redistribution of actin and the tight junction (TJ) proteins, zona occludens-1 and occludin, and the loss of the endothelial cell barrier architecture. Atrial natriuretic peptide (ANP) inhibited VPF signaling, TJ protein phosphorylation and localization, and VPF-induced permeability. This involved both guanylate cyclase and natriuretic peptide clearance receptors. In vivo, transgenic mice that overexpress ANP showed significantly less VPF-induced kinase activation and vascular permeability compared with non-transgenic littermates. Thus, ANP acts as an anti-permeability factor by inhibiting the signaling functions of VPF that we define here and by preserving the endothelial cell TJ functional morphology. Vascular endothelial cell growth factor (VEGF) was originally described as a potent vascular permeability factor (VPF) that importantly contributes to vascular pathobiology. The signaling pathways that underlie VEGF/VPF-induced permeability are not well defined. Furthermore, endogenous vascular peptides that regulate this important VPF function are currently unknown. We report here that VPF significantly enhances permeability in aortic endothelial cells via a linked signaling pathway, sequentially involving Src, ERK, JNK, and phosphatidylinositol 3-kinase/AKT. This leads to the serine/threonine phosphorylation and redistribution of actin and the tight junction (TJ) proteins, zona occludens-1 and occludin, and the loss of the endothelial cell barrier architecture. Atrial natriuretic peptide (ANP) inhibited VPF signaling, TJ protein phosphorylation and localization, and VPF-induced permeability. This involved both guanylate cyclase and natriuretic peptide clearance receptors. In vivo, transgenic mice that overexpress ANP showed significantly less VPF-induced kinase activation and vascular permeability compared with non-transgenic littermates. Thus, ANP acts as an anti-permeability factor by inhibiting the signaling functions of VPF that we define here and by preserving the endothelial cell TJ functional morphology. The vascular endothelial cell growth factor (VEGF) 1The abbreviations used are: VEGF, vascular endothelial cell growth factor; ANP, atrial natriuretic peptide; CNP, C-type natriuretic peptide; ERK, extracellular signal-regulated kinase; JNK, c-Jun N-terminal kinase: NPRC, natriuretic peptide receptor, clearance; NO, nitric oxide; PI3K, phosphatidylinositol 3-kinase; TJ, tight junction; VPF, vascular permeability factor; ZO, zona occludens; DMEM, Dulbecco's modified Eagle's medium; BAEC, bovine aortic endothelial cells; l-NAME, monomethyll-arginine; EC, endothelial cell; BNP, brain natriuretic peptide; NP, natriuretic peptides; PKG, protein kinase G; MAP, mitogen-activated protein; ANOVA, analysis of variance 1The abbreviations used are: VEGF, vascular endothelial cell growth factor; ANP, atrial natriuretic peptide; CNP, C-type natriuretic peptide; ERK, extracellular signal-regulated kinase; JNK, c-Jun N-terminal kinase: NPRC, natriuretic peptide receptor, clearance; NO, nitric oxide; PI3K, phosphatidylinositol 3-kinase; TJ, tight junction; VPF, vascular permeability factor; ZO, zona occludens; DMEM, Dulbecco's modified Eagle's medium; BAEC, bovine aortic endothelial cells; l-NAME, monomethyll-arginine; EC, endothelial cell; BNP, brain natriuretic peptide; NP, natriuretic peptides; PKG, protein kinase G; MAP, mitogen-activated protein; ANOVA, analysis of varianceglycoprotein is an important angiogenesis factor that was originally isolated as a vascular permeability factor (VPF) (1Senger D.R. Galli S.J. Dvorak A.M. Peruzzi C.A. Harvey V.S. Dvorak H.F. Science. 1983; 219: 983-985Crossref PubMed Scopus (3380) Google Scholar, 2Ferrara N. Trends Cardiovasc. Med. 1993; 3: 224-225Crossref Scopus (169) Google Scholar). VEGF/VPF (henceforth designated VPF) potently stimulates fluid transgression through endothelial cell (EC) tight junctions (TJ) (3Milton S.G. Knutson K.P. J. Cell. Physiol. 1990; 144: 498-504Crossref PubMed Scopus (63) Google Scholar, 4Larson D.M. Ryan U.S. Scholar). This permeability factor the and function of in J. Dvorak H.F. Dvorak A.M. J. Physiol. Scopus Google and the of J. PubMed Google Scholar). underlie the vascular permeability in to VPF, is in the with and (1Senger D.R. Galli S.J. Dvorak A.M. Peruzzi C.A. Harvey V.S. Dvorak H.F. Science. 1983; 219: 983-985Crossref PubMed Scopus (3380) Google Scholar, D.M. N. J. PubMed Scopus Google the of N. N. J. Med. PubMed Scopus Google and the J. PubMed Scopus Google of VPF and signaling through the Cell. 1993; PubMed Scopus Google J. J. PubMed Google and Cell. PubMed Scopus Google Scholar). The kinase to in VPF permeability PubMed Scopus Google signaling through to important J. Scopus Google Scholar). as and phosphatidylinositol J. J. PubMed Google Scholar, J. PubMed Scopus Google and is to the of the of VPF in the of brain N. N. J. PubMed Scopus Google Scholar, J. Cell. PubMed Scopus Google Scholar). contributes to the of VPF to J. PubMed Scopus Google in permeability is to the of nitric PubMed Scopus Google Scholar, J. PubMed Scopus Google and activation of the extracellular signal-regulated kinase mitogen-activated protein kinase J. J. J. PubMed Scopus Google PubMed Scopus Google VPF-induced protein kinase J. J. Physiol. Google to to vascular permeability. activation of is a functional permeability is NO, this both protein in cells and the of the actin J. N. J. PubMed Scopus Google Scholar, N. D.M. J. Physiol. Google Scholar, J. PubMed Google Scholar, J. PubMed Scopus Google Scholar). This in the of cell tight junctions to J. PubMed Google Scholar). We as in VPF-induced permeability in the of the J. PubMed Scopus Google Scholar). In VPF signaling pathways in the phosphorylation of TJ that in as zona occludens-1 J. PubMed Scopus Google Scholar). of TJ in a of J. PubMed Google as an of barrier TJ with of this endothelial J. PubMed Scopus Google Scholar, J. Physiol. PubMed Google Scholar). Thus, VPF-induced signaling to the and to TJ is important and to vascular D.M. N. J. PubMed Scopus Google Scholar, N. N. J. Med. PubMed Scopus Google Scholar, J. PubMed Scopus Google to vascular the natriuretic peptides are a of that and as well as vascular in N. J. Med. PubMed Scopus Google Scholar). Atrial and brain natriuretic peptides and are in the C-type natriuretic peptide is by the endothelial peptides vascular cell growth the guanylate cyclase to ANP Scopus Google Scholar, PubMed Scopus Google Scholar). This stimulates the of and activation of PKG, the of N. J. Med. PubMed Scopus Google Scholar). of is the clearance Science. PubMed Scopus Google and this protein to the of vascular endothelial N. J. Med. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, J. Physiol. Google VPF-induced permeability the of D.M. N. J. PubMed Scopus Google Scholar, N. N. J. Med. PubMed Scopus Google Scholar, J. PubMed Scopus Google Scholar, N. N. J. PubMed Scopus Google we a signaling and the in Furthermore, we the as of in in vascular permeability is a to the of and and the and vascular (1Senger D.R. Galli S.J. Dvorak A.M. Peruzzi C.A. Harvey V.S. Dvorak H.F. Science. 1983; 219: 983-985Crossref PubMed Scopus (3380) Google Scholar, D.M. N. J. PubMed Scopus Google Scholar, N. N. J. Med. PubMed Scopus Google Scholar, N. N. J. PubMed Scopus Google Scholar, J. Cell. PubMed Scopus Google Scholar). of contributes to We report that the of VPF to the actin TJ protein phosphorylation and localization, and the permeability barrier function of vascular endothelial cells The kinase of the the of VPF to to and J. PubMed Scopus Google Scholar). of the kinase by VPF J. Physiol. PubMed Google J. PubMed Scopus Google Scholar, J. J. PubMed Scopus Google and N. J. PubMed Scopus Google Scholar). kinase activation in a function of VPF J. PubMed Scopus Google Scholar). We showed that this VPF-induced and cell in J. PubMed Scopus Google Scholar). This through a signaling leads to the activation of and Thus, signaling to the function of this important vascular we define the signaling that are VPF-induced permeability and that the natriuretic peptides functions VPF-induced is to the vascular permeability and that J. Cell. PubMed Scopus Google Scholar, Med. PubMed Scopus Google of is not We that activation is VPF of and and the activation of inhibiting of proteins, we and important signaling of VPF and in the of through the We that kinase and to this of activation of in J. PubMed Scopus Google and activation of endothelial contributes to VPF-induced angiogenesis and vascular permeability J. PubMed Scopus Google Scholar). we that of that J. PubMed Scopus Google activation by in to J. PubMed Scopus Google that in the of VPF, and this in activation and J. PubMed Scopus Google Scholar). We report here a VPF signaling, and and regulate is that growth factor growth factor a to J. Cell. PubMed Scopus Google Scholar). to the protein to both S.J. J. PubMed Scopus Google and of J. Cell. PubMed Scopus Google to the of a signaling S.J. J. PubMed Scopus Google Scholar). are to VPF in that VPF-induced contributes to cell J. PubMed Scopus Google Scholar). The of and by VPF is here in that signaling leads to of the actin and TJ protein localization, and permeability of the In the of the are and this in to the of VPF, by in the N. N. J. Med. PubMed Scopus Google Scholar, N. PubMed Scopus Google Scholar). vascular permeability to and of the VPF-induced signaling that we define here in this by natriuretic VPF-induced signaling in This permeability factor in and stimulates in J. Dvorak H.F. Dvorak A.M. J. Physiol. Scopus Google Scholar, J. PubMed Google Scholar). VPF the transgression of fluid through tight junctions (3Milton S.G. Knutson K.P. J. Cell. Physiol. 1990; 144: 498-504Crossref PubMed Scopus (63) Google Scholar, 4Larson D.M. Ryan U.S. Scholar). The important barrier function of is the of the TJ as the and with J. PubMed Scopus Google PubMed Scopus Google J. PubMed Scopus Google and J. Scopus Google and of with actin cell junctions to a J. J. PubMed Scopus Google Scholar). of the actin the TJ and barrier function J. PubMed Google Scholar, J. J. Physiol. Google Scholar). This leads to the of endothelial cell that are to by VPF J. PubMed Google that VPF a redistribution of and the and this was by that VPF and the tight and cell by J. Physiol. PubMed Google Scholar). we the phosphorylation of TJ by and as the the of the this phosphorylation by signaling by the cells to ANP significantly to the of permeability. J. PubMed Scopus Google in the permeability by VPF, with the loss of and by phosphorylation and redistribution of in J. Physiol. PubMed Google Scholar). In phosphorylation of occludin, to the of the TJ of cells J. PubMed Scopus (169) Google Scholar). phosphorylation of and in to VPF, by J. PubMed Scopus Google Scholar). are and phosphorylation well as and occludin, and a of the TJ and VPF function is showed that VPF signaling through pathways actin in the In this the of NO, linked to and the of tight junctions J. PubMed Scopus Google Scholar, J. N. J. PubMed Scopus Google Scholar, J. PubMed Google Scholar). ANP actin and VPF-induced the of natriuretic peptides to and vascular in N. J. Med. PubMed Scopus Google of this mice aortic compared with N. PubMed Scopus Google Scholar). of ANP are D.M. 1993; PubMed Scopus Google and ANP PubMed Google Scholar). is that in this the to angiogenesis and are PubMed Scopus Google Scholar). is of this protein and in cell ANP, BNP, and to VPF-induced permeability. Thus, the are as the vascular peptides that both VPF and Scholar, J. PubMed Scopus Google Scholar). This is of in that the described of are to VPF and V.S. Dvorak H.F. Med. PubMed Scopus Google of the is by mice ANP permeability and kinase activation VPF of VPF with of the ERK, PI3K, and c-Jun in VPF-induced and this was in the non-transgenic ANP is VPF, as permeability was not ANP transgenic mice are to compared with non-transgenic J. PubMed Scopus Google Scholar). this is to to the anti-permeability of ANP we vivo, permeability was in transgenic of ANP to both and clearance receptors. The and of of ANP to PubMed Scopus Google Scholar). We that a J. N. J. PubMed Scopus Google significantly the of ANP not the and in ANP VPF-induced activation and signaling through this and this a the of ANP via are through activation of protein kinase is not the kinase important in this We that a of the of ANP and the signaling the are the of in N. J. Med. PubMed Scopus Google Scholar). function of the is to Science. PubMed Scopus Google to of ANP, as we a that the important function of VPF to vascular permeability. The signaling leads to the phosphorylation and of protein of the tight peptides as anti-permeability and functions the natriuretic peptides and are in with the of peptides to the to and of to the The vascular endothelial cell growth factor (VEGF) 1The abbreviations used are: VEGF, vascular endothelial cell growth factor; ANP, atrial natriuretic peptide; CNP, C-type natriuretic peptide; ERK, extracellular signal-regulated kinase; JNK, c-Jun N-terminal kinase: NPRC, natriuretic peptide receptor, clearance; NO, nitric oxide; PI3K, phosphatidylinositol 3-kinase; TJ, tight junction; VPF, vascular permeability factor; ZO, zona occludens; DMEM, Dulbecco's modified Eagle's medium; BAEC, bovine aortic endothelial cells; l-NAME, monomethyll-arginine; EC, endothelial cell; BNP, brain natriuretic peptide; NP, natriuretic peptides; PKG, protein kinase G; MAP, mitogen-activated protein; ANOVA, analysis of variance 1The abbreviations used are: VEGF, vascular endothelial cell growth factor; ANP, atrial natriuretic peptide; CNP, C-type natriuretic peptide; ERK, extracellular signal-regulated kinase; JNK, c-Jun N-terminal kinase: NPRC, natriuretic peptide receptor, clearance; NO, nitric oxide; PI3K, phosphatidylinositol 3-kinase; TJ, tight junction; VPF, vascular permeability factor; ZO, zona occludens; DMEM, Dulbecco's modified Eagle's medium; BAEC, bovine aortic endothelial cells; l-NAME, monomethyll-arginine; EC, endothelial cell; BNP, brain natriuretic peptide; NP, natriuretic peptides; PKG, protein kinase G; MAP, mitogen-activated protein; ANOVA, analysis of varianceglycoprotein is an important angiogenesis factor that was originally isolated as a vascular permeability factor (VPF) (1Senger D.R. Galli S.J. Dvorak A.M. Peruzzi C.A. Harvey V.S. Dvorak H.F. Science. 1983; 219: 983-985Crossref PubMed Scopus (3380) Google Scholar, 2Ferrara N. Trends Cardiovasc. Med. 1993; 3: 224-225Crossref Scopus (169) Google Scholar). VEGF/VPF (henceforth designated VPF) potently stimulates fluid transgression through endothelial cell (EC) tight junctions (TJ) (3Milton S.G. Knutson K.P. J. Cell. Physiol. 1990; 144: 498-504Crossref PubMed Scopus (63) Google Scholar, 4Larson D.M. Ryan U.S. Scholar). This permeability factor the and function of in J. Dvorak H.F. Dvorak A.M. J. Physiol. Scopus Google and the of J. PubMed Google Scholar). underlie the vascular permeability in to VPF, is in the with and (1Senger D.R. Galli S.J. Dvorak A.M. Peruzzi C.A. Harvey V.S. Dvorak H.F. Science. 1983; 219: 983-985Crossref PubMed Scopus (3380) Google Scholar, D.M. N. J. PubMed Scopus Google the of N. N. J. Med. PubMed Scopus Google and the J. PubMed Scopus Google Scholar). The of VPF and signaling through the Cell. 1993; PubMed Scopus Google J. J. PubMed Google and Cell. PubMed Scopus Google Scholar). The kinase to in VPF permeability PubMed Scopus Google signaling through to important J. Scopus Google Scholar). as and phosphatidylinositol J. J. PubMed Google Scholar, J. PubMed Scopus Google and is to the of the of VPF in the of brain N. N. J. PubMed Scopus Google Scholar, J. Cell. PubMed Scopus Google Scholar). contributes to the of VPF to J. PubMed Scopus Google in permeability is to the of nitric PubMed Scopus Google Scholar, J. PubMed Scopus Google and activation of the extracellular signal-regulated kinase mitogen-activated protein kinase J. J. J. PubMed Scopus Google PubMed Scopus Google VPF-induced protein kinase J. J. Physiol. Google to to vascular permeability. activation of is a functional permeability is NO, this both protein in cells and the of the actin J. N. J. PubMed Scopus Google Scholar, N. D.M. J. Physiol. Google Scholar, J. PubMed Google Scholar, J. PubMed Scopus Google Scholar). This in the of cell tight junctions to J. PubMed Google Scholar). We as in VPF-induced permeability in the of the J. PubMed Scopus Google Scholar). In VPF signaling pathways in the phosphorylation of TJ that in as zona occludens-1 J. PubMed Scopus Google Scholar). of TJ in a of J. PubMed Google as an of barrier TJ with of this endothelial J. PubMed Scopus Google Scholar, J. Physiol. PubMed Google Scholar). Thus, VPF-induced signaling to the and to TJ is important and to vascular D.M. N. J. PubMed Scopus Google Scholar, N. N. J. Med. PubMed Scopus Google Scholar, J. PubMed Scopus Google Scholar). to vascular the natriuretic peptides are a of that and as well as vascular in N. J. Med. PubMed Scopus Google Scholar). Atrial and brain natriuretic peptides and are in the C-type natriuretic peptide is by the endothelial peptides vascular cell growth the guanylate cyclase to ANP Scopus Google Scholar, PubMed Scopus Google Scholar). This stimulates the of and activation of PKG, the of N. J. Med. PubMed Scopus Google Scholar). of is the clearance Science. PubMed Scopus Google and this protein to the of vascular endothelial N. J. Med. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, J. Physiol. Google Scholar). VPF-induced permeability the of D.M. N. J. PubMed Scopus Google Scholar, N. N. J. Med. PubMed Scopus Google Scholar, J. PubMed Scopus Google Scholar, N. N. J. PubMed Scopus Google we a signaling and the in Furthermore, we the as of in in vascular permeability is a to the of and and the and vascular (1Senger D.R. Galli S.J. Dvorak A.M. Peruzzi C.A. Harvey V.S. Dvorak H.F. Science. 1983; 219: 983-985Crossref PubMed Scopus (3380) Google Scholar, D.M. N. J. PubMed Scopus Google Scholar, N. N. J. Med. PubMed Scopus Google Scholar, N. N. J. PubMed Scopus Google Scholar, J. Cell. PubMed Scopus Google Scholar). of contributes to We report that the of VPF to the actin TJ protein phosphorylation and localization, and the permeability barrier function of vascular endothelial cells The kinase of the the of VPF to to and J. PubMed Scopus Google Scholar). of the kinase by VPF J. Physiol. PubMed Google J. PubMed Scopus Google Scholar, J. J. PubMed Scopus Google and N. J. PubMed Scopus Google Scholar). kinase activation in a function of VPF J. PubMed Scopus Google Scholar). We showed that this VPF-induced and cell in J. PubMed Scopus Google Scholar). This through a signaling leads to the activation of and Thus, signaling to the function of this important vascular we define the signaling that are VPF-induced permeability and that the natriuretic peptides functions VPF-induced is to the vascular permeability and that J. Cell. PubMed Scopus Google Scholar, Med. PubMed Scopus Google of is not We that activation is VPF of and and the activation of inhibiting of proteins, we and important signaling of VPF and in the of through the We that kinase and to this of activation of in J. PubMed Scopus Google and activation of endothelial contributes to VPF-induced angiogenesis and vascular permeability J. PubMed Scopus Google Scholar). we that of that J. PubMed Scopus Google activation by in to J. PubMed Scopus Google that in the of VPF, and this in activation and J. PubMed Scopus Google Scholar). We report here a VPF signaling, and and regulate is that growth factor growth factor a to J. Cell. PubMed Scopus Google Scholar). to the protein to both S.J. J. PubMed Scopus Google and of J. Cell. PubMed Scopus Google to the of a signaling S.J. J. PubMed Scopus Google Scholar). are to VPF in that VPF-induced contributes to cell J. PubMed Scopus Google Scholar). The of and by VPF is here in that signaling leads to of the actin and TJ protein localization, and permeability of the In the of the are and this in to the of VPF, by in the N. N. J. Med. PubMed Scopus Google Scholar, N. PubMed Scopus Google Scholar). vascular permeability to and of the VPF-induced signaling that we define here in this by natriuretic VPF-induced signaling in This permeability factor in and stimulates in J. Dvorak H.F. Dvorak A.M. J. Physiol. Scopus Google Scholar, J. PubMed Google Scholar). VPF the transgression of fluid through tight junctions (3Milton S.G. Knutson K.P. J. Cell. Physiol. 1990; 144: 498-504Crossref PubMed Scopus (63) Google Scholar, 4Larson D.M. Ryan U.S. Scholar). The important barrier function of is the of the TJ as the and with J. PubMed Scopus Google PubMed Scopus Google J. PubMed Scopus Google and J. Scopus Google and of with actin cell junctions to a J. J. PubMed Scopus Google Scholar). of the actin the TJ and barrier function J. PubMed Google Scholar, J. J. Physiol. Google Scholar). This leads to the of endothelial cell that are to by VPF J. PubMed Google that VPF a redistribution of and the and this was by that VPF and the tight and cell by J. Physiol. PubMed Google Scholar). we the phosphorylation of TJ by and as the the of the this phosphorylation by signaling by the cells to ANP significantly to the of permeability. J. PubMed Scopus Google in the permeability by VPF, with the loss of and by phosphorylation and redistribution of in J. Physiol. PubMed Google Scholar). In phosphorylation of occludin, to the of the TJ of cells J. PubMed Scopus (169) Google Scholar). phosphorylation of and in to VPF, by J. PubMed Scopus Google Scholar). are and phosphorylation well as and occludin, and a of the TJ and VPF function is showed that VPF signaling through pathways actin in the In this the of NO, linked to and the of tight junctions J. PubMed Scopus Google Scholar, J. N. J. PubMed Scopus Google Scholar, J. PubMed Google Scholar). ANP actin and VPF-induced the of natriuretic peptides to and vascular in N. J. Med. PubMed Scopus Google of this mice aortic compared with N. PubMed Scopus Google Scholar). of ANP are D.M. 1993; PubMed Scopus Google and ANP PubMed Google Scholar). is that in this the to angiogenesis and are PubMed Scopus Google Scholar). is of this protein and in cell ANP, BNP, and to VPF-induced permeability. Thus, the are as the vascular peptides that both VPF and Scholar, J. PubMed Scopus Google Scholar). This is of in that the described of are to VPF and V.S. Dvorak H.F. Med. PubMed Scopus Google of the is by mice ANP permeability and kinase activation VPF of VPF with of the ERK, PI3K, and c-Jun in VPF-induced and this was in the non-transgenic ANP is VPF, as permeability was not ANP transgenic mice are to compared with non-transgenic J. PubMed Scopus Google Scholar). this is to to the anti-permeability of ANP we vivo, permeability was in transgenic of ANP to both and clearance receptors. The and of of ANP to PubMed Scopus Google Scholar). We that a J. N. J. PubMed Scopus Google significantly the of ANP not the and in ANP VPF-induced activation and signaling through this and this a the of ANP via are through activation of protein kinase is not the kinase important in this We that a of the of ANP and the signaling the are the of in N. J. Med. PubMed Scopus Google Scholar). function of the is to Science. PubMed Scopus Google to of ANP, as we a that the important function of VPF to vascular permeability. The signaling leads to the phosphorylation and of protein of the tight peptides as anti-permeability and functions the natriuretic peptides and are in with the of peptides to the to and of to the VPF-induced vascular permeability is a to the of and and the and vascular (1Senger D.R. Galli S.J. Dvorak A.M. Peruzzi C.A. Harvey V.S. Dvorak H.F. Science. 1983; 219: 983-985Crossref PubMed Scopus (3380) Google Scholar, D.M. N. J. PubMed Scopus Google Scholar, N. N. J. Med. PubMed Scopus Google Scholar, N. N. J. PubMed Scopus Google Scholar, J. Cell. PubMed Scopus Google Scholar). of contributes to We report that the of VPF to the actin TJ protein phosphorylation and localization, and the permeability barrier function of vascular endothelial cells The kinase of the the of VPF to to and J. PubMed Scopus Google Scholar). of the kinase by VPF J. Physiol. PubMed Google J. PubMed Scopus Google Scholar, J. J. PubMed Scopus Google and N. J. PubMed Scopus Google Scholar). kinase activation in a function of VPF J. PubMed Scopus Google Scholar). We showed that this VPF-induced and cell in J. PubMed Scopus Google Scholar). This through a signaling leads to the activation of and Thus, signaling to the function of this important vascular we define the signaling that are VPF-induced permeability and that the natriuretic peptides functions VPF-induced is to the vascular permeability and that J. Cell. PubMed Scopus Google Scholar, Med. PubMed Scopus Google of is not We that activation is VPF of and and the activation of inhibiting of proteins, we and important signaling of VPF and in the of through the We that kinase and to this of activation of in J. PubMed Scopus Google and activation of endothelial contributes to VPF-induced angiogenesis and vascular permeability J. PubMed Scopus Google Scholar). we that of that J. PubMed Scopus Google activation by in to J. PubMed Scopus Google Scholar). We that in the of VPF, and this in activation and J. PubMed Scopus Google Scholar). We report here a VPF signaling, and and regulate is that growth factor growth factor a to J. Cell. PubMed Scopus Google Scholar). to the protein to both S.J. J. PubMed Scopus Google and of J. Cell. PubMed Scopus Google to the of a signaling S.J. J. PubMed Scopus Google Scholar). are to VPF in that VPF-induced contributes to cell J. PubMed Scopus Google Scholar). The of and by VPF is here in that signaling leads to of the actin and TJ protein localization, and permeability of the In the of the are and this in to the of VPF, by in the N. N. J. Med. PubMed Scopus Google Scholar, N. PubMed Scopus Google Scholar). vascular permeability to and of the VPF-induced signaling that we define here in this by natriuretic VPF-induced signaling in This permeability factor in and stimulates in J. Dvorak H.F. Dvorak A.M. J. Physiol. Scopus Google Scholar, J. PubMed Google Scholar). VPF the transgression of fluid through tight junctions (3Milton S.G. Knutson K.P. J. Cell. Physiol. 1990; 144: 498-504Crossref PubMed Scopus (63) Google Scholar, 4Larson D.M. Ryan U.S. Scholar). The important barrier function of is the of the TJ as the and with J. PubMed Scopus Google PubMed Scopus Google J. PubMed Scopus Google and J. Scopus Google and of with actin cell junctions to a J. J. PubMed Scopus Google Scholar). of the actin the TJ and barrier function J. PubMed Google Scholar, J. J. Physiol. Google Scholar). This leads to the of endothelial cell that are to by VPF J. PubMed Google Scholar). We that VPF a redistribution of and the and this was by that VPF and the tight and cell by J. Physiol. PubMed Google Scholar). we the phosphorylation of TJ by and as the the of the this phosphorylation by signaling by the cells to ANP significantly to the of permeability. J. PubMed Scopus Google in the permeability by VPF, with the loss of and by phosphorylation and redistribution of in J. Physiol. PubMed Google Scholar). In phosphorylation of occludin, to the of the TJ of cells J. PubMed Scopus (169) Google Scholar). phosphorylation of and in to VPF, by J. PubMed Scopus Google Scholar). are and phosphorylation well as and occludin, and a of the TJ and VPF function is We showed that VPF signaling through pathways actin in the In this the of NO, linked to and the of tight junctions J. PubMed Scopus Google Scholar, J. N. J. PubMed Scopus Google Scholar, J. PubMed Google Scholar). ANP actin and VPF-induced the of natriuretic peptides to and vascular in N. J. Med. PubMed Scopus Google Scholar). In of this mice aortic compared with N. PubMed Scopus Google Scholar). of ANP are D.M. 1993; PubMed Scopus Google and ANP PubMed Google Scholar). is that in this the to angiogenesis and are PubMed Scopus Google Scholar). is of this protein and in cell ANP, BNP, and to VPF-induced permeability. Thus, the are as the vascular peptides that both VPF and Scholar, J. PubMed Scopus Google Scholar). This is of in that the described of are to VPF and V.S. Dvorak H.F. Med. PubMed Scopus Google Scholar). The of the is by mice ANP permeability and kinase activation VPF of VPF with of the ERK, PI3K, and c-Jun in VPF-induced and this was in the non-transgenic ANP is VPF, as permeability was not ANP transgenic mice are to compared with non-transgenic J. PubMed Scopus Google Scholar). this is to to the anti-permeability of ANP we vivo, permeability was in transgenic The of ANP to both and clearance receptors. The and of of ANP to PubMed Scopus Google Scholar). We that a J. N. J. PubMed Scopus Google significantly the of ANP not the and in ANP VPF-induced activation and signaling through this and this a the of ANP via are through activation of protein kinase is not the kinase important in this We that a of the of ANP and the signaling the are the of in N. J. Med. PubMed Scopus Google Scholar). function of the is to Science. PubMed Scopus Google to of ANP, as In we a that the important function of VPF to vascular permeability. The signaling leads to the phosphorylation and of protein of the tight peptides as anti-permeability and functions the natriuretic peptides and are in with the of peptides to the to and of to the We of the