The Experts below are selected from a list of 1053 Experts worldwide ranked by ideXlab platform
Hongyu Luo - One of the best experts on this subject based on the ideXlab platform.
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the receptor tyrosine kinase ephb6 regulates catecholamine exocytosis in adrenal gland chromaffin cells
Journal of Biological Chemistry, 2020Co-Authors: Wei Shi, Marion Rame, Yujia Wang, Dominique Cioca, Sophie Reibel, Junzheng Peng, Nicolas Vitale, Hongyu LuoAbstract:The erythropoietin-producing human hepatocellular receptor EPH receptor B6 (EPHB6) is a receptor tyrosine kinase that has been shown previously to control catecholamine synthesis in the adrenal gland chromaffin cells (AGCCs) in a testosterone-dependent fashion. EPHB6 also has a role in regulating blood pressure, but several facets of this regulation remain unclear. Using amperometry recordings, we now found that catecholamine secretion by AGCCs is compromised in the absence of EPHB6. AGCCs from male knockout (KO) mice displayed reduced cortical F-actin disassembly, accompanied by decreased catecholamine secretion through exocytosis. This phenotype was not observed in AGCCs from female KO mice, suggesting that testosterone, but not estrogen, contributes to this phenotype. Of note, reverse signaling from EPHB6 to ephrin B1 (EFNB1) and a 7-amino acid-long segment in the EFNB1 intracellular tail were essential for the regulation of catecholamine secretion. Further downstream, the Ras homolog family member A (RHOA) and FYN proto-oncogene Src family tyrosine kinase (FYN)-proto-oncogene c-ABL-microtubule-associated monooxygenase calponin and LIM domain containing 1 (MICAL-1) pathways mediated the signaling from EFNB1 to the defective F-actin disassembly. We discuss the implications of EPHB6's effect on catecholamine exocytosis and secretion for blood pressure regulation.
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the role of grip1 and ephrin b3 in blood pressure control and vascular smooth muscle cell contractility
Scientific Reports, 2016Co-Authors: Yujia Wang, Junzheng Peng, Hongyu Luo, John Verner Raelson, Georg Ehret, Patricia B Munroe, Ekatherina Stoyanova, Zhao Qin, Guy Cloutier, Edward W C BradleyAbstract:Several erythropoietin-producing hepatocellular receptor B family (EPHB) and their ligands, ephrinBs (EFNBs), are involved in blood pressure regulation in animal models. We selected 528 single nucleotide polymorphisms (SNPs) within the genes of EPHB6, EFNB2, EFNB3 and GRIP1 in the EPH/EFN signalling system to query the International Blood Pressure Consortium dataset. A SNP within the glutamate receptor interacting protein 1 (GRIP1) gene presented a p-value of 0.000389, approaching the critical p-value of 0.000302, for association with diastolic blood pressure of 60,396 individuals. According to echocardiography, we found that Efnb3 gene knockout mice showed enhanced constriction in the carotid arteries. In vitro studies revealed that in mouse vascular smooth muscle cells, siRNA knockdown of GRIP1, which is in the EFNB3 reverse signalling pathway, resulted in increased contractility of these cells. These data suggest that molecules in the EPHB/EFNB signalling pathways, specifically EFNB3 and GRIP1, are involved blood pressure regulation.
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ephb4 protein expression in vascular smooth muscle cells regulates their contractility and ephb4 deletion leads to hypotension in mice
Journal of Biological Chemistry, 2015Co-Authors: Yujia Wang, Hongyu Luo, Eric Thorin, Johanne Tremblay, Julie L Lavoie, Junzheng PengAbstract:EPH kinases are the largest family of receptor tyrosine kinases, and their ligands, ephrins (EFNs), are also cell surface molecules. This work presents evidence that EPHB4 on vascular smooth muscle cells (VSMCs) is involved in blood pressure regulation. We generated gene KO mice with smooth muscle cell-specific deletion of EPHB4. Male KO mice, but not female KO mice, were hypotensive. VSMCs from male KO mice showed reduced contractility when compared with their WT counterparts. Signaling both from EFNBs to EPHB4 (forward signaling) and from EPHB4 to EFNB2 (reverse signaling) modulated VSMC contractility. At the molecular level, the absence of EPHB4 in VSMCs resulted in compromised signaling from Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) to myosin light chain kinase (MLCK) to myosin light chain, the last of which controls the contraction force of motor molecule myosin. Near the cell membrane, an adaptor protein GRIP1, which can associate with EFNB2, was found to be essential in mediating EPHB4-to-EFNB reverse signaling, which regulated VSMC contractility, based on siRNA gene knockdown studies. Our research indicates that EPHB4 plays an essential role in regulating small artery contractility and blood pressure.
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ephb4 protein expression in vascular smooth muscle cells regulates their contractility and ephb4 deletion leads to hypotension in mice
Journal of Biological Chemistry, 2015Co-Authors: Yujia Wang, Hongyu Luo, Eric Thorin, Johanne Tremblay, Julie L Lavoie, Junzheng PengAbstract:EPH kinases are the largest family of receptor tyrosine kinases, and their ligands, ephrins (EFNs), are also cell surface molecules. This work presents evidence that EPHB4 on vascular smooth muscle cells (VSMCs) is involved in blood pressure regulation. We generated gene KO mice with smooth muscle cell-specific deletion of EPHB4. Male KO mice, but not female KO mice, were hypotensive. VSMCs from male KO mice showed reduced contractility when compared with their WT counterparts. Signaling both from EFNBs to EPHB4 (forward signaling) and from EPHB4 to EFNB2 (reverse signaling) modulated VSMC contractility. At the molecular level, the absence of EPHB4 in VSMCs resulted in compromised signaling from Ca2+/calmodulin-dependent protein kinase II (CaMKII) to myosin light chain kinase (MLCK) to myosin light chain, the last of which controls the contraction force of motor molecule myosin. Near the cell membrane, an adaptor protein GRIP1, which can associate with EFNB2, was found to be essential in mediating EPHB4-to-EFNB reverse signaling, which regulated VSMC contractility, based on siRNA gene knockdown studies. Our research indicates that EPHB4 plays an essential role in regulating small artery contractility and blood pressure. Background: The role of EPHB4 blood pressure regulation was not previously known. Results: Male but not female smooth muscle cell-specific Ephb4 gene knock-out mice were hypotensive; bi-directional signaling between EFNBs and EPHB4 modulated small artery contractility. Conclusion: EPHB4 in vascular smooth muscle cells regulates blood pressure. Significance: A new mechanism of blood pressure regulation has been discovered.
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Possible Role of EFNB1 Protein, a Ligand of Eph Receptor Tyrosine Kinases, in Modulating Blood Pressure
The Journal of biological chemistry, 2012Co-Authors: Hongyu Luo, Junzheng Peng, Eric Thorin, Johanne Tremblay, Julie L Lavoie, Yujia WangAbstract:Eph kinases constitute the largest receptor tyrosine kinase family, and their ligands, ephrins (Efns), are also cell surface molecules. Although they are ligands, Efns can transduce signals reversely into cells. We have no prior knowledge of the role played by any members of this family of kinases or their ligands in blood pressure (BP) regulation. In the present studies, we investigated the role of EFNB1 in vascular smooth muscle cell (VSMC) contractility and BP regulation. We revealed that reverse signaling through EFNB1 led to a reduction of RhoA activation and VSMC contractility in vitro. Consistent with this finding, ex vivo, there was an increase of RhoA activity accompanied by augmented myosin light chain phosphorylation in mesenteric arteries from mice with smooth muscle-specific conditional EFNB1 gene knock-out (KO). Small interfering RNA knockdown of Grip1, a molecule associated with the EFNB1 intracellular tail, partially eliminated the effect of EFNB1 on VSMC contractility and myosin light chain phosphorylation. In support of these in vitro and ex vivo results, EFNB1 KO mice on a high salt diet showed a statistically significant heightened increment of BP at multiple time points during stress compared with wild type littermates. Our results demonstrate that EFNB1 is a previously unknown negative regulator of VSMC contractility and BP and that it exerts such effects via reverse signaling through Grip1.
Yujia Wang - One of the best experts on this subject based on the ideXlab platform.
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the receptor tyrosine kinase ephb6 regulates catecholamine exocytosis in adrenal gland chromaffin cells
Journal of Biological Chemistry, 2020Co-Authors: Wei Shi, Marion Rame, Yujia Wang, Dominique Cioca, Sophie Reibel, Junzheng Peng, Nicolas Vitale, Hongyu LuoAbstract:The erythropoietin-producing human hepatocellular receptor EPH receptor B6 (EPHB6) is a receptor tyrosine kinase that has been shown previously to control catecholamine synthesis in the adrenal gland chromaffin cells (AGCCs) in a testosterone-dependent fashion. EPHB6 also has a role in regulating blood pressure, but several facets of this regulation remain unclear. Using amperometry recordings, we now found that catecholamine secretion by AGCCs is compromised in the absence of EPHB6. AGCCs from male knockout (KO) mice displayed reduced cortical F-actin disassembly, accompanied by decreased catecholamine secretion through exocytosis. This phenotype was not observed in AGCCs from female KO mice, suggesting that testosterone, but not estrogen, contributes to this phenotype. Of note, reverse signaling from EPHB6 to ephrin B1 (EFNB1) and a 7-amino acid-long segment in the EFNB1 intracellular tail were essential for the regulation of catecholamine secretion. Further downstream, the Ras homolog family member A (RHOA) and FYN proto-oncogene Src family tyrosine kinase (FYN)-proto-oncogene c-ABL-microtubule-associated monooxygenase calponin and LIM domain containing 1 (MICAL-1) pathways mediated the signaling from EFNB1 to the defective F-actin disassembly. We discuss the implications of EPHB6's effect on catecholamine exocytosis and secretion for blood pressure regulation.
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Analysis of the association of EPHB6, EFNB1 and EFNB3 variants with hypertension risks in males with hypogonadism.
Scientific reports, 2018Co-Authors: Bi-qi Zhang, Yujia Wang, John Verner Raelson, Yu-mei Yao, Francois-christophe Marois-blanchet, Muhammad Ramzan Tahir, W. Edward C. BradleyAbstract:Several members of the EPH kinase family and their ligands are involved in blood pressure regulation, and such regulation is often sex- or sex hormone-dependent, based on animal and human genetic studies. EPHB6 gene knockout (KO) in mice leads to hypertension in castrated males but not in un-manipulated KO males or females. To assess whether this finding in mice is relevant to human hypertension, we conducted a human genetic study for the association of EPHB6 and its two ligands, EFNB1 and EFNB3, with hypertension in hypogonadic patients. Seven hundred and fifty hypertensive and 750 normotensive Han Chinese patients, all of whom were hypogonadic, were genotyped for single nucleotide polymorphisms (SNPs) within the regions of the genes, plus an additional 50 kb 5′ of the genes for EPHB6, EFNB1 and EFNB3. An imputed insertion/deletion polymorphism, rs35530071, was found to be associated with hypertension at p-values below the Bonferroni-corrected significance level of 0.0024. This marker is located 5′ upstream of the EFNB3 gene start site. Previous animal studies showed that while male EFNB3 gene knockout mice were normotensive, castration of these mice resulted in hypertension, corroborating the results of the human genetic study. Considering the significant associations of EFNB3 SNPs with hypertension in hypogonadic males and supporting evidence from castrated EFNB3 KO mice, we conclude that loss-of-function variants of molecules in the EPHB6 signaling pathway in the presence of testosterone are protective against hypertension in humans.
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the role of grip1 and ephrin b3 in blood pressure control and vascular smooth muscle cell contractility
Scientific Reports, 2016Co-Authors: Yujia Wang, Junzheng Peng, Hongyu Luo, John Verner Raelson, Georg Ehret, Patricia B Munroe, Ekatherina Stoyanova, Zhao Qin, Guy Cloutier, Edward W C BradleyAbstract:Several erythropoietin-producing hepatocellular receptor B family (EPHB) and their ligands, ephrinBs (EFNBs), are involved in blood pressure regulation in animal models. We selected 528 single nucleotide polymorphisms (SNPs) within the genes of EPHB6, EFNB2, EFNB3 and GRIP1 in the EPH/EFN signalling system to query the International Blood Pressure Consortium dataset. A SNP within the glutamate receptor interacting protein 1 (GRIP1) gene presented a p-value of 0.000389, approaching the critical p-value of 0.000302, for association with diastolic blood pressure of 60,396 individuals. According to echocardiography, we found that Efnb3 gene knockout mice showed enhanced constriction in the carotid arteries. In vitro studies revealed that in mouse vascular smooth muscle cells, siRNA knockdown of GRIP1, which is in the EFNB3 reverse signalling pathway, resulted in increased contractility of these cells. These data suggest that molecules in the EPHB/EFNB signalling pathways, specifically EFNB3 and GRIP1, are involved blood pressure regulation.
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ephb4 protein expression in vascular smooth muscle cells regulates their contractility and ephb4 deletion leads to hypotension in mice
Journal of Biological Chemistry, 2015Co-Authors: Yujia Wang, Hongyu Luo, Eric Thorin, Johanne Tremblay, Julie L Lavoie, Junzheng PengAbstract:EPH kinases are the largest family of receptor tyrosine kinases, and their ligands, ephrins (EFNs), are also cell surface molecules. This work presents evidence that EPHB4 on vascular smooth muscle cells (VSMCs) is involved in blood pressure regulation. We generated gene KO mice with smooth muscle cell-specific deletion of EPHB4. Male KO mice, but not female KO mice, were hypotensive. VSMCs from male KO mice showed reduced contractility when compared with their WT counterparts. Signaling both from EFNBs to EPHB4 (forward signaling) and from EPHB4 to EFNB2 (reverse signaling) modulated VSMC contractility. At the molecular level, the absence of EPHB4 in VSMCs resulted in compromised signaling from Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) to myosin light chain kinase (MLCK) to myosin light chain, the last of which controls the contraction force of motor molecule myosin. Near the cell membrane, an adaptor protein GRIP1, which can associate with EFNB2, was found to be essential in mediating EPHB4-to-EFNB reverse signaling, which regulated VSMC contractility, based on siRNA gene knockdown studies. Our research indicates that EPHB4 plays an essential role in regulating small artery contractility and blood pressure.
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ephb4 protein expression in vascular smooth muscle cells regulates their contractility and ephb4 deletion leads to hypotension in mice
Journal of Biological Chemistry, 2015Co-Authors: Yujia Wang, Hongyu Luo, Eric Thorin, Johanne Tremblay, Julie L Lavoie, Junzheng PengAbstract:EPH kinases are the largest family of receptor tyrosine kinases, and their ligands, ephrins (EFNs), are also cell surface molecules. This work presents evidence that EPHB4 on vascular smooth muscle cells (VSMCs) is involved in blood pressure regulation. We generated gene KO mice with smooth muscle cell-specific deletion of EPHB4. Male KO mice, but not female KO mice, were hypotensive. VSMCs from male KO mice showed reduced contractility when compared with their WT counterparts. Signaling both from EFNBs to EPHB4 (forward signaling) and from EPHB4 to EFNB2 (reverse signaling) modulated VSMC contractility. At the molecular level, the absence of EPHB4 in VSMCs resulted in compromised signaling from Ca2+/calmodulin-dependent protein kinase II (CaMKII) to myosin light chain kinase (MLCK) to myosin light chain, the last of which controls the contraction force of motor molecule myosin. Near the cell membrane, an adaptor protein GRIP1, which can associate with EFNB2, was found to be essential in mediating EPHB4-to-EFNB reverse signaling, which regulated VSMC contractility, based on siRNA gene knockdown studies. Our research indicates that EPHB4 plays an essential role in regulating small artery contractility and blood pressure. Background: The role of EPHB4 blood pressure regulation was not previously known. Results: Male but not female smooth muscle cell-specific Ephb4 gene knock-out mice were hypotensive; bi-directional signaling between EFNBs and EPHB4 modulated small artery contractility. Conclusion: EPHB4 in vascular smooth muscle cells regulates blood pressure. Significance: A new mechanism of blood pressure regulation has been discovered.
Junzheng Peng - One of the best experts on this subject based on the ideXlab platform.
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the receptor tyrosine kinase ephb6 regulates catecholamine exocytosis in adrenal gland chromaffin cells
Journal of Biological Chemistry, 2020Co-Authors: Wei Shi, Marion Rame, Yujia Wang, Dominique Cioca, Sophie Reibel, Junzheng Peng, Nicolas Vitale, Hongyu LuoAbstract:The erythropoietin-producing human hepatocellular receptor EPH receptor B6 (EPHB6) is a receptor tyrosine kinase that has been shown previously to control catecholamine synthesis in the adrenal gland chromaffin cells (AGCCs) in a testosterone-dependent fashion. EPHB6 also has a role in regulating blood pressure, but several facets of this regulation remain unclear. Using amperometry recordings, we now found that catecholamine secretion by AGCCs is compromised in the absence of EPHB6. AGCCs from male knockout (KO) mice displayed reduced cortical F-actin disassembly, accompanied by decreased catecholamine secretion through exocytosis. This phenotype was not observed in AGCCs from female KO mice, suggesting that testosterone, but not estrogen, contributes to this phenotype. Of note, reverse signaling from EPHB6 to ephrin B1 (EFNB1) and a 7-amino acid-long segment in the EFNB1 intracellular tail were essential for the regulation of catecholamine secretion. Further downstream, the Ras homolog family member A (RHOA) and FYN proto-oncogene Src family tyrosine kinase (FYN)-proto-oncogene c-ABL-microtubule-associated monooxygenase calponin and LIM domain containing 1 (MICAL-1) pathways mediated the signaling from EFNB1 to the defective F-actin disassembly. We discuss the implications of EPHB6's effect on catecholamine exocytosis and secretion for blood pressure regulation.
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the role of grip1 and ephrin b3 in blood pressure control and vascular smooth muscle cell contractility
Scientific Reports, 2016Co-Authors: Yujia Wang, Junzheng Peng, Hongyu Luo, John Verner Raelson, Georg Ehret, Patricia B Munroe, Ekatherina Stoyanova, Zhao Qin, Guy Cloutier, Edward W C BradleyAbstract:Several erythropoietin-producing hepatocellular receptor B family (EPHB) and their ligands, ephrinBs (EFNBs), are involved in blood pressure regulation in animal models. We selected 528 single nucleotide polymorphisms (SNPs) within the genes of EPHB6, EFNB2, EFNB3 and GRIP1 in the EPH/EFN signalling system to query the International Blood Pressure Consortium dataset. A SNP within the glutamate receptor interacting protein 1 (GRIP1) gene presented a p-value of 0.000389, approaching the critical p-value of 0.000302, for association with diastolic blood pressure of 60,396 individuals. According to echocardiography, we found that Efnb3 gene knockout mice showed enhanced constriction in the carotid arteries. In vitro studies revealed that in mouse vascular smooth muscle cells, siRNA knockdown of GRIP1, which is in the EFNB3 reverse signalling pathway, resulted in increased contractility of these cells. These data suggest that molecules in the EPHB/EFNB signalling pathways, specifically EFNB3 and GRIP1, are involved blood pressure regulation.
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Role of EFNB1 and EFNB2 in Mouse Collagen-Induced Arthritis and Human Rheumatoid Arthritis
Arthritis & rheumatology (Hoboken N.J.), 2015Co-Authors: Xuehai Wang, Baoli Cheng, Xiangming Fang, Johanne Martel-pelletier, Mohit Kapoor, Junzheng PengAbstract:Objective EFNB1 and EFNB2 are ligands for Eph receptor tyrosine kinases. This study was undertaken to investigate how the expression of EFNB1 and Efnb2 on murine T cells influences the pathogenesis of collagen-induced arthritis (CIA) and to assess correlations between the T cell expression of these 2 molecules and measures of disease activity in patients with rheumatoid arthritis (RA). Methods CIA was studied in mice with T cell–specific deletion (double gene knockout [dKO]) of both EFNB1 and Efnb2. Expression of EFNB1 and EFNB2 messenger RNA (mRNA) in peripheral blood T cells from patients with RA was determined by quantitative reverse transcription– polymerase chain reaction. Results In dKO mice, clinical scores of arthritis were reduced compared to those in wild-type (WT) control mice. Serum collagen-specific antibody titers in dKO mice were lower than those in WT mice. In analyses based on equal cell numbers, dKO mouse T cells, as compared to WT mouse T cells, provided vastly inferior help to B cells in the production of collagen-specific antibodies in vitro. T cells from dKO mice were compromised in their ability to migrate to the arthritic paws in vivo and in their ability to undergo chemotaxis toward CXCL12 in vitro. Deletion mutation of EFNB1 and Efnb2 intracellular tails revealed critical regions in controlling T cell chemotaxis. T cells from RA patients expressed higher EFNB1 mRNA levels, which correlated with RA symptoms and laboratory findings. Conclusion EFNB1 and Efnb2 in T cells are essential for pathogenic antibody production and for T cell migration to the inflamed paws in mice with CIA. These findings suggest that the expression of EFNB1 in T cells might be a useful parameter for monitoring RA disease activity and treatment responses.
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ephb4 protein expression in vascular smooth muscle cells regulates their contractility and ephb4 deletion leads to hypotension in mice
Journal of Biological Chemistry, 2015Co-Authors: Yujia Wang, Hongyu Luo, Eric Thorin, Johanne Tremblay, Julie L Lavoie, Junzheng PengAbstract:EPH kinases are the largest family of receptor tyrosine kinases, and their ligands, ephrins (EFNs), are also cell surface molecules. This work presents evidence that EPHB4 on vascular smooth muscle cells (VSMCs) is involved in blood pressure regulation. We generated gene KO mice with smooth muscle cell-specific deletion of EPHB4. Male KO mice, but not female KO mice, were hypotensive. VSMCs from male KO mice showed reduced contractility when compared with their WT counterparts. Signaling both from EFNBs to EPHB4 (forward signaling) and from EPHB4 to EFNB2 (reverse signaling) modulated VSMC contractility. At the molecular level, the absence of EPHB4 in VSMCs resulted in compromised signaling from Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) to myosin light chain kinase (MLCK) to myosin light chain, the last of which controls the contraction force of motor molecule myosin. Near the cell membrane, an adaptor protein GRIP1, which can associate with EFNB2, was found to be essential in mediating EPHB4-to-EFNB reverse signaling, which regulated VSMC contractility, based on siRNA gene knockdown studies. Our research indicates that EPHB4 plays an essential role in regulating small artery contractility and blood pressure.
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ephb4 protein expression in vascular smooth muscle cells regulates their contractility and ephb4 deletion leads to hypotension in mice
Journal of Biological Chemistry, 2015Co-Authors: Yujia Wang, Hongyu Luo, Eric Thorin, Johanne Tremblay, Julie L Lavoie, Junzheng PengAbstract:EPH kinases are the largest family of receptor tyrosine kinases, and their ligands, ephrins (EFNs), are also cell surface molecules. This work presents evidence that EPHB4 on vascular smooth muscle cells (VSMCs) is involved in blood pressure regulation. We generated gene KO mice with smooth muscle cell-specific deletion of EPHB4. Male KO mice, but not female KO mice, were hypotensive. VSMCs from male KO mice showed reduced contractility when compared with their WT counterparts. Signaling both from EFNBs to EPHB4 (forward signaling) and from EPHB4 to EFNB2 (reverse signaling) modulated VSMC contractility. At the molecular level, the absence of EPHB4 in VSMCs resulted in compromised signaling from Ca2+/calmodulin-dependent protein kinase II (CaMKII) to myosin light chain kinase (MLCK) to myosin light chain, the last of which controls the contraction force of motor molecule myosin. Near the cell membrane, an adaptor protein GRIP1, which can associate with EFNB2, was found to be essential in mediating EPHB4-to-EFNB reverse signaling, which regulated VSMC contractility, based on siRNA gene knockdown studies. Our research indicates that EPHB4 plays an essential role in regulating small artery contractility and blood pressure. Background: The role of EPHB4 blood pressure regulation was not previously known. Results: Male but not female smooth muscle cell-specific Ephb4 gene knock-out mice were hypotensive; bi-directional signaling between EFNBs and EPHB4 modulated small artery contractility. Conclusion: EPHB4 in vascular smooth muscle cells regulates blood pressure. Significance: A new mechanism of blood pressure regulation has been discovered.
Johanne Tremblay - One of the best experts on this subject based on the ideXlab platform.
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ephb4 protein expression in vascular smooth muscle cells regulates their contractility and ephb4 deletion leads to hypotension in mice
Journal of Biological Chemistry, 2015Co-Authors: Yujia Wang, Hongyu Luo, Eric Thorin, Johanne Tremblay, Julie L Lavoie, Junzheng PengAbstract:EPH kinases are the largest family of receptor tyrosine kinases, and their ligands, ephrins (EFNs), are also cell surface molecules. This work presents evidence that EPHB4 on vascular smooth muscle cells (VSMCs) is involved in blood pressure regulation. We generated gene KO mice with smooth muscle cell-specific deletion of EPHB4. Male KO mice, but not female KO mice, were hypotensive. VSMCs from male KO mice showed reduced contractility when compared with their WT counterparts. Signaling both from EFNBs to EPHB4 (forward signaling) and from EPHB4 to EFNB2 (reverse signaling) modulated VSMC contractility. At the molecular level, the absence of EPHB4 in VSMCs resulted in compromised signaling from Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) to myosin light chain kinase (MLCK) to myosin light chain, the last of which controls the contraction force of motor molecule myosin. Near the cell membrane, an adaptor protein GRIP1, which can associate with EFNB2, was found to be essential in mediating EPHB4-to-EFNB reverse signaling, which regulated VSMC contractility, based on siRNA gene knockdown studies. Our research indicates that EPHB4 plays an essential role in regulating small artery contractility and blood pressure.
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ephb4 protein expression in vascular smooth muscle cells regulates their contractility and ephb4 deletion leads to hypotension in mice
Journal of Biological Chemistry, 2015Co-Authors: Yujia Wang, Hongyu Luo, Eric Thorin, Johanne Tremblay, Julie L Lavoie, Junzheng PengAbstract:EPH kinases are the largest family of receptor tyrosine kinases, and their ligands, ephrins (EFNs), are also cell surface molecules. This work presents evidence that EPHB4 on vascular smooth muscle cells (VSMCs) is involved in blood pressure regulation. We generated gene KO mice with smooth muscle cell-specific deletion of EPHB4. Male KO mice, but not female KO mice, were hypotensive. VSMCs from male KO mice showed reduced contractility when compared with their WT counterparts. Signaling both from EFNBs to EPHB4 (forward signaling) and from EPHB4 to EFNB2 (reverse signaling) modulated VSMC contractility. At the molecular level, the absence of EPHB4 in VSMCs resulted in compromised signaling from Ca2+/calmodulin-dependent protein kinase II (CaMKII) to myosin light chain kinase (MLCK) to myosin light chain, the last of which controls the contraction force of motor molecule myosin. Near the cell membrane, an adaptor protein GRIP1, which can associate with EFNB2, was found to be essential in mediating EPHB4-to-EFNB reverse signaling, which regulated VSMC contractility, based on siRNA gene knockdown studies. Our research indicates that EPHB4 plays an essential role in regulating small artery contractility and blood pressure. Background: The role of EPHB4 blood pressure regulation was not previously known. Results: Male but not female smooth muscle cell-specific Ephb4 gene knock-out mice were hypotensive; bi-directional signaling between EFNBs and EPHB4 modulated small artery contractility. Conclusion: EPHB4 in vascular smooth muscle cells regulates blood pressure. Significance: A new mechanism of blood pressure regulation has been discovered.
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Possible Role of EFNB1 Protein, a Ligand of Eph Receptor Tyrosine Kinases, in Modulating Blood Pressure
The Journal of biological chemistry, 2012Co-Authors: Hongyu Luo, Junzheng Peng, Eric Thorin, Johanne Tremblay, Julie L Lavoie, Yujia WangAbstract:Eph kinases constitute the largest receptor tyrosine kinase family, and their ligands, ephrins (Efns), are also cell surface molecules. Although they are ligands, Efns can transduce signals reversely into cells. We have no prior knowledge of the role played by any members of this family of kinases or their ligands in blood pressure (BP) regulation. In the present studies, we investigated the role of EFNB1 in vascular smooth muscle cell (VSMC) contractility and BP regulation. We revealed that reverse signaling through EFNB1 led to a reduction of RhoA activation and VSMC contractility in vitro. Consistent with this finding, ex vivo, there was an increase of RhoA activity accompanied by augmented myosin light chain phosphorylation in mesenteric arteries from mice with smooth muscle-specific conditional EFNB1 gene knock-out (KO). Small interfering RNA knockdown of Grip1, a molecule associated with the EFNB1 intracellular tail, partially eliminated the effect of EFNB1 on VSMC contractility and myosin light chain phosphorylation. In support of these in vitro and ex vivo results, EFNB1 KO mice on a high salt diet showed a statistically significant heightened increment of BP at multiple time points during stress compared with wild type littermates. Our results demonstrate that EFNB1 is a previously unknown negative regulator of VSMC contractility and BP and that it exerts such effects via reverse signaling through Grip1.
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receptor tyrosine kinase ephb6 regulates vascular smooth muscle contractility and modulates blood pressure in concert with sex hormones
Journal of Biological Chemistry, 2012Co-Authors: Hongyu Luo, Junzheng Peng, Ekatherina Stoyanova, Guy Cloutier, Eric Thorin, Johanne Tremblay, Julie L Lavoie, Mark J CameronAbstract:Abstract Eph kinases constitute the largest receptor tyrosine kinase family, and their ligands, ephrins (Efns), are also cell surface molecules. Our study is the first to assess the role of Ephb6 in blood pressure (BP) regulation. We observed that EphB6 and all three of its Efnb ligands were expressed on vascular smooth muscle cells (VSMC) in mice. We discovered that small arteries from castrated Ephb6 gene KO males showed increased contractility, RhoA activation, and constitutive myosin light chain phosphorylation ex vivo compared with their WT counterparts. Consistent with this finding, castrated Ephb6 KO mice presented heightened BP compared with castrated WT controls. In vitro experiments in VSMC revealed that cross-linking Efnbs but not Ephb6 resulted in reduced VSMC contractions, suggesting that reverse signaling through Efnbs was responsible for the observed BP phenotype. The reverse signaling was mediated by an adaptor protein Grip1. Additional experiments demonstrated decreased 24-h urine catecholamines in male Ephb6 KO mice, probably as a compensatory feedback mechanism to keep their BP in the normal range. After castration, however, such compensation was abolished in Ephb6 KO mice and was likely the reason why BP increased overtly in these animals. It suggests that Ephb6 has a target in the nervous/endocrine system in addition to VSMC, regulating a testosterone-dependent catecholamine compensatory mechanism. Our study discloses that Ephs and Efns, in concert with testosterone, play a critical role in regulating small artery contractility and BP.
Eric Thorin - One of the best experts on this subject based on the ideXlab platform.
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ephb4 protein expression in vascular smooth muscle cells regulates their contractility and ephb4 deletion leads to hypotension in mice
Journal of Biological Chemistry, 2015Co-Authors: Yujia Wang, Hongyu Luo, Eric Thorin, Johanne Tremblay, Julie L Lavoie, Junzheng PengAbstract:EPH kinases are the largest family of receptor tyrosine kinases, and their ligands, ephrins (EFNs), are also cell surface molecules. This work presents evidence that EPHB4 on vascular smooth muscle cells (VSMCs) is involved in blood pressure regulation. We generated gene KO mice with smooth muscle cell-specific deletion of EPHB4. Male KO mice, but not female KO mice, were hypotensive. VSMCs from male KO mice showed reduced contractility when compared with their WT counterparts. Signaling both from EFNBs to EPHB4 (forward signaling) and from EPHB4 to EFNB2 (reverse signaling) modulated VSMC contractility. At the molecular level, the absence of EPHB4 in VSMCs resulted in compromised signaling from Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) to myosin light chain kinase (MLCK) to myosin light chain, the last of which controls the contraction force of motor molecule myosin. Near the cell membrane, an adaptor protein GRIP1, which can associate with EFNB2, was found to be essential in mediating EPHB4-to-EFNB reverse signaling, which regulated VSMC contractility, based on siRNA gene knockdown studies. Our research indicates that EPHB4 plays an essential role in regulating small artery contractility and blood pressure.
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ephb4 protein expression in vascular smooth muscle cells regulates their contractility and ephb4 deletion leads to hypotension in mice
Journal of Biological Chemistry, 2015Co-Authors: Yujia Wang, Hongyu Luo, Eric Thorin, Johanne Tremblay, Julie L Lavoie, Junzheng PengAbstract:EPH kinases are the largest family of receptor tyrosine kinases, and their ligands, ephrins (EFNs), are also cell surface molecules. This work presents evidence that EPHB4 on vascular smooth muscle cells (VSMCs) is involved in blood pressure regulation. We generated gene KO mice with smooth muscle cell-specific deletion of EPHB4. Male KO mice, but not female KO mice, were hypotensive. VSMCs from male KO mice showed reduced contractility when compared with their WT counterparts. Signaling both from EFNBs to EPHB4 (forward signaling) and from EPHB4 to EFNB2 (reverse signaling) modulated VSMC contractility. At the molecular level, the absence of EPHB4 in VSMCs resulted in compromised signaling from Ca2+/calmodulin-dependent protein kinase II (CaMKII) to myosin light chain kinase (MLCK) to myosin light chain, the last of which controls the contraction force of motor molecule myosin. Near the cell membrane, an adaptor protein GRIP1, which can associate with EFNB2, was found to be essential in mediating EPHB4-to-EFNB reverse signaling, which regulated VSMC contractility, based on siRNA gene knockdown studies. Our research indicates that EPHB4 plays an essential role in regulating small artery contractility and blood pressure. Background: The role of EPHB4 blood pressure regulation was not previously known. Results: Male but not female smooth muscle cell-specific Ephb4 gene knock-out mice were hypotensive; bi-directional signaling between EFNBs and EPHB4 modulated small artery contractility. Conclusion: EPHB4 in vascular smooth muscle cells regulates blood pressure. Significance: A new mechanism of blood pressure regulation has been discovered.
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Possible Role of EFNB1 Protein, a Ligand of Eph Receptor Tyrosine Kinases, in Modulating Blood Pressure
The Journal of biological chemistry, 2012Co-Authors: Hongyu Luo, Junzheng Peng, Eric Thorin, Johanne Tremblay, Julie L Lavoie, Yujia WangAbstract:Eph kinases constitute the largest receptor tyrosine kinase family, and their ligands, ephrins (Efns), are also cell surface molecules. Although they are ligands, Efns can transduce signals reversely into cells. We have no prior knowledge of the role played by any members of this family of kinases or their ligands in blood pressure (BP) regulation. In the present studies, we investigated the role of EFNB1 in vascular smooth muscle cell (VSMC) contractility and BP regulation. We revealed that reverse signaling through EFNB1 led to a reduction of RhoA activation and VSMC contractility in vitro. Consistent with this finding, ex vivo, there was an increase of RhoA activity accompanied by augmented myosin light chain phosphorylation in mesenteric arteries from mice with smooth muscle-specific conditional EFNB1 gene knock-out (KO). Small interfering RNA knockdown of Grip1, a molecule associated with the EFNB1 intracellular tail, partially eliminated the effect of EFNB1 on VSMC contractility and myosin light chain phosphorylation. In support of these in vitro and ex vivo results, EFNB1 KO mice on a high salt diet showed a statistically significant heightened increment of BP at multiple time points during stress compared with wild type littermates. Our results demonstrate that EFNB1 is a previously unknown negative regulator of VSMC contractility and BP and that it exerts such effects via reverse signaling through Grip1.
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receptor tyrosine kinase ephb6 regulates vascular smooth muscle contractility and modulates blood pressure in concert with sex hormones
Journal of Biological Chemistry, 2012Co-Authors: Hongyu Luo, Junzheng Peng, Ekatherina Stoyanova, Guy Cloutier, Eric Thorin, Johanne Tremblay, Julie L Lavoie, Mark J CameronAbstract:Abstract Eph kinases constitute the largest receptor tyrosine kinase family, and their ligands, ephrins (Efns), are also cell surface molecules. Our study is the first to assess the role of Ephb6 in blood pressure (BP) regulation. We observed that EphB6 and all three of its Efnb ligands were expressed on vascular smooth muscle cells (VSMC) in mice. We discovered that small arteries from castrated Ephb6 gene KO males showed increased contractility, RhoA activation, and constitutive myosin light chain phosphorylation ex vivo compared with their WT counterparts. Consistent with this finding, castrated Ephb6 KO mice presented heightened BP compared with castrated WT controls. In vitro experiments in VSMC revealed that cross-linking Efnbs but not Ephb6 resulted in reduced VSMC contractions, suggesting that reverse signaling through Efnbs was responsible for the observed BP phenotype. The reverse signaling was mediated by an adaptor protein Grip1. Additional experiments demonstrated decreased 24-h urine catecholamines in male Ephb6 KO mice, probably as a compensatory feedback mechanism to keep their BP in the normal range. After castration, however, such compensation was abolished in Ephb6 KO mice and was likely the reason why BP increased overtly in these animals. It suggests that Ephb6 has a target in the nervous/endocrine system in addition to VSMC, regulating a testosterone-dependent catecholamine compensatory mechanism. Our study discloses that Ephs and Efns, in concert with testosterone, play a critical role in regulating small artery contractility and BP.