The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Andrew J Bryant - One of the best experts on this subject based on the ideXlab platform.
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Vascular Endothelial Cell specific connective tissue growth factor ctgf is necessary for development of chronic hypoxia induced pulmonary hypertension
Frontiers in Physiology, 2018Co-Authors: Liya Pi, Yuanquing Lu, Junmei Zhou, Chunhua Fu, Marda Jorgensen, Kenneth E Lipson, Edward W Scott, Vinayak Shenoy, Andrew J BryantAbstract:Chronic hypoxia frequently complicates the care of patients with interstitial lung disease, contributing to the development of pulmonary hypertension (PH), and premature death. Connective tissue growth factor (CTGF), a matriCellular protein of the Cyr61/CTGF/Nov (CCN) family, is known to exacerbate Vascular remodeling within the lung. We have previously demonstrated that Vascular Endothelial-Cell specific down-regulation of CTGF is associated with protection against the development of PH associated with hypoxia, though the mechanism for this effect is unknown. In this study, we generated a transgenic mouse line in which the Ctgf gene was floxed and deleted in Vascular Endothelial Cells that expressed Cre recombinase under the control of VE-Cadherin promoter (eCTGF KO mice). Lack of Vascular Endothelial-derived CTGF protected against the development of PH secondary to chronic hypoxia, as well as in another model of bleomycin-induced pulmonary hypertension. Importantly, attenuation of PH was associated with a decrease in infiltrating inflammatory Cells expressing CD11b or integrin M (ITGAM), a known adhesion receptor for CTGF, in the lungs of hypoxia-exposed eCTGF KO mice. Moreover, these pathological changes were associated with activation of – Rho GTPase family member – Cell division control protein 42 homolog (Cdc42) signaling, known to be associated with alteration in Endothelial barrier function. These data indicate that Endothelial-specific deletion of CTGF results in protection against development of chronic-hypoxia induced PH. This protection is conferred by both a decrease in inflammatory Cell recruitment to the lung, and a reduction in lung Cdc42 activity. Based on our studies, CTGF inhibitor treatment should be investigated in patients with PH associated with chronic hypoxia secondary to chronic lung disease.
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Vascular Endothelial Cell specific connective tissue growth factor ctgf is necessary for development of chronic hypoxia induced pulmonary hypertension
Frontiers in Physiology, 2018Co-Authors: Liya Pi, Yuanquing Lu, Junmei Zhou, Chunhua Fu, Marda Jorgensen, Kenneth E Lipson, Edward W Scott, Vinayak Shenoy, Andrew J BryantAbstract:Chronic hypoxia frequently complicates the care of patients with interstitial lung disease, contributing to the development of pulmonary hypertension (PH), and premature death. Connective tissue growth factor (CTGF), a matriCellular protein of the Cyr61/CTGF/Nov (CCN) family, is known to exacerbate Vascular remodeling within the lung. We have previously demonstrated that Vascular Endothelial-Cell specific down-regulation of CTGF is associated with protection against the development of PH associated with hypoxia, though the mechanism for this effect is unknown. In this study, we generated a transgenic mouse line in which the Ctgf gene was floxed and deleted in Vascular Endothelial Cells that expressed Cre recombinase under the control of VE-Cadherin promoter (eCTGF KO mice). Lack of Vascular Endothelial-derived CTGF protected against the development of PH secondary to chronic hypoxia, as well as in another model of bleomycin-induced pulmonary hypertension. Importantly, attenuation of PH was associated with a decrease in infiltrating inflammatory Cells expressing CD11b or integrin M (ITGAM), a known adhesion receptor for CTGF, in the lungs of hypoxia-exposed eCTGF KO mice. Moreover, these pathological changes were associated with activation of – Rho GTPase family member – Cell division control protein 42 homolog (Cdc42) signaling, known to be associated with alteration in Endothelial barrier function. These data indicate that Endothelial-specific deletion of CTGF results in protection against development of chronic-hypoxia induced PH. This protection is conferred by both a decrease in inflammatory Cell recruitment to the lung, and a reduction in lung Cdc42 activity. Based on our studies, CTGF inhibitor treatment should be investigated in patients with PH associated with chronic hypoxia secondary to chronic lung disease.
David B Donner - One of the best experts on this subject based on the ideXlab platform.
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tumor necrosis factor employs a protein tyrosine phosphatase to inhibit activation of kdr and Vascular Endothelial Cell growth factor induced Endothelial Cell proliferation
Journal of Biological Chemistry, 2000Co-Authors: Li Wha Wu, James D Dunbar, Osman N Ozes, Lindsey D Mayo, Kelly M Kessler, Jason A Gustin, Melinda R Baerwald, Eric A Jaffe, Robert S Warren, David B DonnerAbstract:Abstract Vascular Endothelial Cell growth factor (VEGF) binds to and promotes the activation of one of its receptors, KDR. Once activated, KDR induces the tyrosine phosphorylation of cytoplasmic signaling proteins that are important to Endothelial Cell proliferation. In human umbilical vein Endothelial Cells (HUVECs), tumor necrosis factor (TNF) inhibits the phosphorylation and activation of KDR. The ability of TNF to diminish VEGF-stimulated KDR activity was impaired by sodium orthovanadate, suggesting that the inhibitory activity of TNF was mediated by a protein-tyrosine phosphatase. KDR-initiated responses specifically associated with Endothelial Cell proliferation, mitogen-activated protein kinase activation and DNA synthesis, were also inhibited by TNF, and this was reversed by sodium orthovanadate. Stimulation of HUVECs with TNF induced association of the SHP-1 protein-tyrosine phosphatase with KDR, identifying this phosphatase as a candidate negative regulator of VEGF signal transduction. Heterologous receptor inactivation mediated by a protein-tyrosine phosphatase provides insight into how TNF may inhibit Endothelial Cell proliferative responses and modulate angiogenesis in pathological settings.
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Homeostatic Modulation of Cell Surface KDR and Flt1 Expression and Expression of the Vascular Endothelial Cell Growth Factor (VEGF) Receptor mRNAs by VEGF
Journal of Biological Chemistry, 2000Co-Authors: Dongfang Wang, David B Donner, Robert S WarrenAbstract:Vascular Endothelial Cell growth factor (VEGF) is a potent angiogenic factor expressed during embryonic development, during wound healing, and in pathologies dependent on neoVascularization, including cancer. Regulation of the receptor tyrosine kinases, KDR and Flt-1, to which VEGF binds on Endothelial Cells is incompletely understood. Chronic incubation with tumor-conditioned medium or VEGF diminished (125)I-VEGF binding to human umbilical vein Endothelial Cells, incorporation of (125)I-VEGF into covalent complexes with KDR and Flt1, and immunoreactive KDR in Cell lysates. Receptor down-regulation desensitized VEGF activation of mitogen-activated protein kinase (extraCellular signal-regulated kinases 1 and 2) and p38 mitogen-activated protein kinase. Preincubation with VEGF or tumor-conditioned medium down-regulated Cell surface receptor expression but up-regulated KDR and Flt-1 mRNAs, an effect abrogated by a neutralizing VEGF antibody. Removal of VEGF from the medium led to recovery of (125)I-VEGF binding and resensitization of human umbilical vein Endothelial Cells. Recovery of receptor expression was inhibited by cycloheximide, indicating that augmented VEGF receptor mRNAs, and not receptor recycling from a cytoplasmic pool, restored responsiveness. As the VEGF receptors promote Endothelial Cell survival, proliferation, and other events necessary for angiogenesis, the noncoordinate regulation of VEGF receptor proteins and mRNAs suggests that human umbilical vein Endothelial Cells are protected against inappropriate or prolonged loss of VEGF receptors by a homeostatic mechanism important to Endothelial Cell function.
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utilization of distinct signaling pathways by receptors for Vascular Endothelial Cell growth factor and other mitogens in the induction of Endothelial Cell proliferation
Journal of Biological Chemistry, 2000Co-Authors: Li Wha Wu, James D Dunbar, Lindsey D Mayo, Kelly M Kessler, Melinda R Baerwald, Eric A Jaffe, Robert S Warren, Dongfang Wang, David B DonnerAbstract:Abstract This study was initiated to identify signaling proteins used by the receptors for Vascular Endothelial Cell growth factor KDR/Flk1, and Flt1. Two-hybrid cloning and immunoprecipitation from human umbilical vein Endothelial Cells (HUVEC) showed that KDR binds to and promotes the tyrosine phosphorylation of phospholipase Cγ (PLCγ). Neither placental growth factor, which activates Flt1, epidermal growth factor (EGF), or fibroblast growth factor (FGF) induced tyrosine phosphorylation of PLCγ, indicating that KDR is uniquely important to PLCγ activation in HUVEC. By signaling through KDR, VEGF promoted the tyrosine phosphorylation of focal adhesion kinase, induced activation of Akt, protein kinase Ce (PKCe), mitogen-activated protein kinase (MAPK), and promoted thymidine incorporation into DNA. VEGF activates PLCγ, PKCe, and phosphatidylinositol 3-kinase independently of one another. MEK, PLCγ, and to a lesser extent PKC, are in the pathway through which KDR activates MAPK. PLCγ or PKC inhibitors did not affect FGF- or EGF-mediated MAPK activation. MAPK/ERK kinase inhibition diminished VEGF-, FGF-, and EGF-promoted thymidine incorporation into DNA. However, blockade of PKC diminished thymidine incorporation into DNA induced by VEGF but not FGF or EGF. Signaling through KDR/Flk1 activates signaling pathways not utilized by other mitogens to induce proliferation of HUVEC.
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Vascular Endothelial Cell growth factor promotes tyrosine phosphorylation of mediators of signal transduction that contain sh2 domains association with Endothelial Cell proliferation
Journal of Biological Chemistry, 1995Co-Authors: Hoyeong Song, Robert S Warren, David B DonnerAbstract:Abstract Vascular Endothelial Cell growth factor (VEGF), an Endothelial Cell-specific mitogen that plays an important role in angiogenesis, promotes the tyrosine phosphorylation of at least 11 proteins in bovine aortic Endothelial Cells (BAEC). Proteins immunoprecipitated from lysates of control- and VEGF-stimulated BAEC with antisera to phospholipase C- (PLC-) were fractionated by SDS-polyacrylamide gel electrophoresis and transferred to Immobilon-P. Evaluation of the Western blots with antisera to phosphotyrosine demonstrated that PLC- and two proteins (100 and 85 kDa) that associate with PLC- were phosphorylated in response to VEGF. By using antisera specific to other mediators of signal transduction that contain SH2 domains for immunoprecipitation, it was demonstrated that VEGF promotes phosphorylation of phosphatidylinositol 3-kinase, Ras GTPase activating protein (GAP), and the oncogenic adaptor protein NcK. Proteins of Mr consistent with the VEGF receptors Flt-1 and Flk-1/KDR were also tyrosine phosphorylated in stimulated Cells. Tyrosine-phosphorylated Nck, PLC-, and two GAP-associated proteins, p190 and p62, were in GAP immunoprecipitates of VEGF-stimulated BAEC, and tyrosine-phosphorylated NcK was in phosphatidylinositol 3-kinase immunoprecipitates. These observations suggest that VEGF promotes formation of multimeric aggregates of VEGF receptors with proteins that contain SH2 domains and activate various signaling pathways. VEGF-promoted proliferation of Endothelial Cells and tyrosine phosphorylation of SH2 domain containing signaling molecules were inhibited by the tyrosine kinase inhibitor genistein.
Liya Pi - One of the best experts on this subject based on the ideXlab platform.
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Vascular Endothelial Cell specific connective tissue growth factor ctgf is necessary for development of chronic hypoxia induced pulmonary hypertension
Frontiers in Physiology, 2018Co-Authors: Liya Pi, Yuanquing Lu, Junmei Zhou, Chunhua Fu, Marda Jorgensen, Kenneth E Lipson, Edward W Scott, Vinayak Shenoy, Andrew J BryantAbstract:Chronic hypoxia frequently complicates the care of patients with interstitial lung disease, contributing to the development of pulmonary hypertension (PH), and premature death. Connective tissue growth factor (CTGF), a matriCellular protein of the Cyr61/CTGF/Nov (CCN) family, is known to exacerbate Vascular remodeling within the lung. We have previously demonstrated that Vascular Endothelial-Cell specific down-regulation of CTGF is associated with protection against the development of PH associated with hypoxia, though the mechanism for this effect is unknown. In this study, we generated a transgenic mouse line in which the Ctgf gene was floxed and deleted in Vascular Endothelial Cells that expressed Cre recombinase under the control of VE-Cadherin promoter (eCTGF KO mice). Lack of Vascular Endothelial-derived CTGF protected against the development of PH secondary to chronic hypoxia, as well as in another model of bleomycin-induced pulmonary hypertension. Importantly, attenuation of PH was associated with a decrease in infiltrating inflammatory Cells expressing CD11b or integrin M (ITGAM), a known adhesion receptor for CTGF, in the lungs of hypoxia-exposed eCTGF KO mice. Moreover, these pathological changes were associated with activation of – Rho GTPase family member – Cell division control protein 42 homolog (Cdc42) signaling, known to be associated with alteration in Endothelial barrier function. These data indicate that Endothelial-specific deletion of CTGF results in protection against development of chronic-hypoxia induced PH. This protection is conferred by both a decrease in inflammatory Cell recruitment to the lung, and a reduction in lung Cdc42 activity. Based on our studies, CTGF inhibitor treatment should be investigated in patients with PH associated with chronic hypoxia secondary to chronic lung disease.
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Vascular Endothelial Cell specific connective tissue growth factor ctgf is necessary for development of chronic hypoxia induced pulmonary hypertension
Frontiers in Physiology, 2018Co-Authors: Liya Pi, Yuanquing Lu, Junmei Zhou, Chunhua Fu, Marda Jorgensen, Kenneth E Lipson, Edward W Scott, Vinayak Shenoy, Andrew J BryantAbstract:Chronic hypoxia frequently complicates the care of patients with interstitial lung disease, contributing to the development of pulmonary hypertension (PH), and premature death. Connective tissue growth factor (CTGF), a matriCellular protein of the Cyr61/CTGF/Nov (CCN) family, is known to exacerbate Vascular remodeling within the lung. We have previously demonstrated that Vascular Endothelial-Cell specific down-regulation of CTGF is associated with protection against the development of PH associated with hypoxia, though the mechanism for this effect is unknown. In this study, we generated a transgenic mouse line in which the Ctgf gene was floxed and deleted in Vascular Endothelial Cells that expressed Cre recombinase under the control of VE-Cadherin promoter (eCTGF KO mice). Lack of Vascular Endothelial-derived CTGF protected against the development of PH secondary to chronic hypoxia, as well as in another model of bleomycin-induced pulmonary hypertension. Importantly, attenuation of PH was associated with a decrease in infiltrating inflammatory Cells expressing CD11b or integrin M (ITGAM), a known adhesion receptor for CTGF, in the lungs of hypoxia-exposed eCTGF KO mice. Moreover, these pathological changes were associated with activation of – Rho GTPase family member – Cell division control protein 42 homolog (Cdc42) signaling, known to be associated with alteration in Endothelial barrier function. These data indicate that Endothelial-specific deletion of CTGF results in protection against development of chronic-hypoxia induced PH. This protection is conferred by both a decrease in inflammatory Cell recruitment to the lung, and a reduction in lung Cdc42 activity. Based on our studies, CTGF inhibitor treatment should be investigated in patients with PH associated with chronic hypoxia secondary to chronic lung disease.
Ellis R Levin - One of the best experts on this subject based on the ideXlab platform.
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deciphering Vascular Endothelial Cell growth factor Vascular permeability factor signaling to Vascular permeability inhibition by atrial natriuretic peptide
Journal of Biological Chemistry, 2002Co-Authors: Ali Pedram, Mahnaz Razandi, Ellis R LevinAbstract: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.
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role of Vascular Endothelial Cell growth factor in ovarian hyperstimulation syndrome
Journal of Clinical Investigation, 1998Co-Authors: Ellis R Levin, Gregory F Rosen, Denise L Cassidenti, Bill Yee, David R Meldrum, Arthur Wisot, Ali PedramAbstract:Controlled ovarian hyperstimulation with gonadotropins is followed by Ovarian Hyperstimulation Syndrome (OHSS) in some women. An unidentified capillary permeability factor from the ovary has been implicated, and Vascular Endothelial Cell growth/permeability factor (VEGF) is a candidate protein. Follicular fluids (FF) from 80 women who received hormonal induction for infertility were studied. FFs were grouped according to oocyte production, from group I (0-7 oocytes) through group IV (23-31 oocytes). Group IV was comprised of four women with the most severe symptoms of OHSS. Endothelial Cell (EC) permeability induced by the individual FF was highly correlated to oocytes produced (r2 = 0.73, P < 0.001). Group IV FF stimulated a 63+/-4% greater permeability than FF from group I patients (P < 0. 01), reversed 98% by anti-VEGF antibody. Group IV fluids contained the VEGF165 isoform and significantly greater concentrations of VEGF as compared with group I (1,105+/-87 pg/ml vs. 353+/-28 pg/ml, P < 0. 05). Significant cytoskeletal rearrangement of F-actin into stress fibers and a destruction of ZO-1 tight junction protein alignment was caused by group IV FF, mediated in part by nitric oxide. These mechanisms, which lead to increased EC permeability, were reversed by the VEGF antibody. Our results indicate that VEGF is the FF factor responsible for increased Vascular permeability, thereby contributing to the pathogenesis of OHSS.
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extraCellular signal regulated protein kinase jun kinase cross talk underlies Vascular Endothelial Cell growth factor induced Endothelial Cell proliferation
Journal of Biological Chemistry, 1998Co-Authors: Ali Pedram, Mahnaz Razandi, Ellis R LevinAbstract:Abstract Ligand binding to Vascular Endothelial Cell growth factor (VEGF) receptors activates the mitogen-activated protein kinases extraCellular signal-regulated kinase (ERK) and c-Jun N-terminal protein kinase (JNK). Possible cross-communication of ERK and JNK effecting Endothelial Cell (EC) actions of VEGF is poorly understood. Incubation of EC with PD 98059, a specific mitogen-activated protein kinase kinase inhibitor, or transfection with Y185F, a dominant negative ERK2, strongly inhibited VEGF-activated JNK. JNK was also activated by ERK2 expression in the absence of VEGF, inhibited 82% by co-transfection with dominant negative SEK-1, indicating upstream activation of JNK by ERK. VEGF-stimulated JNK activity was also reversed by dominant negative SEK-1. Other EC growth factors exhibited similar cross-activation of JNK through ERK. VEGF stimulated the nuclear incorporation of thymidine, reversed 89% by PD 98059 and 72% by Y185F. Dominant negative SEK-1 or JNK-1 also significantly reduced VEGF-stimulated thymidine incorporation. Expression of wild type Jip-1, which prevents JNK nuclear translocation, inhibited VEGF-induced EC proliferation by 75%. VEGF stimulated both cyclin D1 synthesis and Cdk4 kinase activity, inhibited by PD 98059 and dominant negative JNK-1. Important events for VEGF-induced G1/S progression and Cell proliferation are enhanced through a novel ERK to JNK cross-activation and subsequent JNK action.
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vasoactive peptides modulate Vascular Endothelial Cell growth factor production and Endothelial Cell proliferation and invasion
Journal of Biological Chemistry, 1997Co-Authors: Ali Pedram, Mahnaz Razandi, Renming Hu, Ellis R LevinAbstract:Abstract The proliferation of Vascular Endothelial Cells (EC) is an important event in angiogenesis. The synthesis of the EC growth factor, Vascular Endothelial Cell growth factor (VEGF), is stimulated by a variety of activators; but the effects of important vasoactive peptides are not well understood, and there are no known natural inhibitors of VEGF production. We found that the vasoactive peptides endothelin (ET)-1 and ET-3 stimulated the synthesis of VEGF protein 3–4-fold in cultured human Vascular smooth muscle Cells, comparable in magnitude to hypoxia. ET-1 and ET-3 acted through the ETA and ETB receptors, respectively, and signaling through protein kinase C was important. Atrial natriuretic peptide (ANP), C-type natriuretic peptide, and C-ANP-(4–23), a ligand for the natriuretic peptide clearance receptor, equipotently inhibited production of VEGF by as much as 88% and inhibited ET- or hypoxia-stimulated VEGF transcription. EC proliferation and invasion of matrix were stimulated by VEGF secreted into the medium by ET-incubated Vascular smooth muscle Cells. This was inhibited by ANP. Our results identify the natriuretic peptides as the first peptide inhibitors of VEGF synthesis and indicate a novel mechanism by which vasoactive peptides could modulate angiogenesis.
Kenneth E Lipson - One of the best experts on this subject based on the ideXlab platform.
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Vascular Endothelial Cell specific connective tissue growth factor ctgf is necessary for development of chronic hypoxia induced pulmonary hypertension
Frontiers in Physiology, 2018Co-Authors: Liya Pi, Yuanquing Lu, Junmei Zhou, Chunhua Fu, Marda Jorgensen, Kenneth E Lipson, Edward W Scott, Vinayak Shenoy, Andrew J BryantAbstract:Chronic hypoxia frequently complicates the care of patients with interstitial lung disease, contributing to the development of pulmonary hypertension (PH), and premature death. Connective tissue growth factor (CTGF), a matriCellular protein of the Cyr61/CTGF/Nov (CCN) family, is known to exacerbate Vascular remodeling within the lung. We have previously demonstrated that Vascular Endothelial-Cell specific down-regulation of CTGF is associated with protection against the development of PH associated with hypoxia, though the mechanism for this effect is unknown. In this study, we generated a transgenic mouse line in which the Ctgf gene was floxed and deleted in Vascular Endothelial Cells that expressed Cre recombinase under the control of VE-Cadherin promoter (eCTGF KO mice). Lack of Vascular Endothelial-derived CTGF protected against the development of PH secondary to chronic hypoxia, as well as in another model of bleomycin-induced pulmonary hypertension. Importantly, attenuation of PH was associated with a decrease in infiltrating inflammatory Cells expressing CD11b or integrin M (ITGAM), a known adhesion receptor for CTGF, in the lungs of hypoxia-exposed eCTGF KO mice. Moreover, these pathological changes were associated with activation of – Rho GTPase family member – Cell division control protein 42 homolog (Cdc42) signaling, known to be associated with alteration in Endothelial barrier function. These data indicate that Endothelial-specific deletion of CTGF results in protection against development of chronic-hypoxia induced PH. This protection is conferred by both a decrease in inflammatory Cell recruitment to the lung, and a reduction in lung Cdc42 activity. Based on our studies, CTGF inhibitor treatment should be investigated in patients with PH associated with chronic hypoxia secondary to chronic lung disease.
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Vascular Endothelial Cell specific connective tissue growth factor ctgf is necessary for development of chronic hypoxia induced pulmonary hypertension
Frontiers in Physiology, 2018Co-Authors: Liya Pi, Yuanquing Lu, Junmei Zhou, Chunhua Fu, Marda Jorgensen, Kenneth E Lipson, Edward W Scott, Vinayak Shenoy, Andrew J BryantAbstract:Chronic hypoxia frequently complicates the care of patients with interstitial lung disease, contributing to the development of pulmonary hypertension (PH), and premature death. Connective tissue growth factor (CTGF), a matriCellular protein of the Cyr61/CTGF/Nov (CCN) family, is known to exacerbate Vascular remodeling within the lung. We have previously demonstrated that Vascular Endothelial-Cell specific down-regulation of CTGF is associated with protection against the development of PH associated with hypoxia, though the mechanism for this effect is unknown. In this study, we generated a transgenic mouse line in which the Ctgf gene was floxed and deleted in Vascular Endothelial Cells that expressed Cre recombinase under the control of VE-Cadherin promoter (eCTGF KO mice). Lack of Vascular Endothelial-derived CTGF protected against the development of PH secondary to chronic hypoxia, as well as in another model of bleomycin-induced pulmonary hypertension. Importantly, attenuation of PH was associated with a decrease in infiltrating inflammatory Cells expressing CD11b or integrin M (ITGAM), a known adhesion receptor for CTGF, in the lungs of hypoxia-exposed eCTGF KO mice. Moreover, these pathological changes were associated with activation of – Rho GTPase family member – Cell division control protein 42 homolog (Cdc42) signaling, known to be associated with alteration in Endothelial barrier function. These data indicate that Endothelial-specific deletion of CTGF results in protection against development of chronic-hypoxia induced PH. This protection is conferred by both a decrease in inflammatory Cell recruitment to the lung, and a reduction in lung Cdc42 activity. Based on our studies, CTGF inhibitor treatment should be investigated in patients with PH associated with chronic hypoxia secondary to chronic lung disease.
