The Experts below are selected from a list of 1938 Experts worldwide ranked by ideXlab platform
Marta Tesone - One of the best experts on this subject based on the ideXlab platform.
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metformin regulates ovarian angiogenesis and follicular development in a female polycystic ovary syndrome rat model
Endocrinology, 2015Co-Authors: Mariana Di Pietro, Fernanda Parborell, Griselda Irusta, Marta Tesone, Diana Bas, Natalia Pascuali, Maria Silvia Bianchi, Dalhia AbramovichAbstract:Polycystic ovary syndrome (PCOS) is a frequent pathology that affects more than 5% of women of reproductive age. Among other heterogeneous symptoms, PCOS is characterized by abnormalities in angiogenesis. Metformin has been introduced in the treatment of PCOS to manage insulin resistance and hyperglycemia. Besides its metabolic effects, metformin has been shown to improve ovulation, pregnancy and live birth rates in PCOS patients. In the present study, we used a dehydroepiandrosterone-induced PCOS rat model to analyze the effect of metformin administration on ovarian angiogenesis. We found that metformin was able to restore the increased levels of vascular endothelial growth factor, angiopoietin (ANGPT)1, and ANGPT1/ANGPT2 ratio and the decreased levels of platelet-derived growth factor B and platelet-derived growth factor D observed in the dehydroepiandrosterone-treated rats. These effects could take place, at least in part, through a decrease in the levels of serum insulin. We also found an improvement in follicular development, with a lower percentage of small follicles and cysts and a higher percentage of antral follicles and corpora lutea after metformin administration. The improvement in ovarian angiogenesis is likely to restore the accumulation of small follicles observed in PCOS rats and to reduce cyst formation, thus improving follicular development and the percentage of corpora lutea. These results open new insights into the study of metformin action not only in glucose metabolism but also in ovarian dysfunction in PCOS women.
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angiopoietins tie2 system and vegf are involved in ovarian function in a dhea rat model of polycystic ovary syndrome
Endocrinology, 2012Co-Authors: Fernanda Parborell, Dalhia Abramovich, Griselda Irusta, Marta Tesone, Natalia I Cataldi, Diana BasAbstract:Polycystic ovary syndrome (PCOS) is the most common endocrinological pathology among women of reproductive age. It is characterized by anovulation, oligo- or amenorrhea, hyperandrogenism, obesity, and insulin resistance. PCOS patients present with elevated levels of vascular endothelial growth factor (VEGF) in serum and follicular fluid. In this study, we examined the ovarian expression of angiopoietins (ANGPT) and their receptor tyrosine kinase receptor (TIE2), involved in the stabilization of blood vessels, in a rat model of dehydroepiandrosterone-induced PCOS. We also analyzed the effect of ovarian VEGF inhibition on ANGPT/TIE2, follicular development, and vascular stability. VEGF levels were increased in the PCOS ovaries, whereas the levels of its receptor fetal liver kinase-1 were decreased. In addition, the periendothelial cell area and the ANGPT1 to ANGPT2 ratio in the ovary were increased in the PCOS group. Percentage of primary follicles was increased and the percentage of preantral follicles and corpora lutea was decreased in the PCOS group. VEGF inhibition decreased the percentage of primary follicles close to control values. Interestingly, despite the presence of cysts in the ovaries from VEGF inhibitor-treated PCOS rats, its percentage was lower than the PCOS group without treatment. In summary, this study describes an alteration not only in the VEGF/fetal liver kinase-1 system but also in the ANGPT/TIE2 system in a dehydroepiandrosterone-induced PCOS rat model. This leads to an increase in periendothelial cell recruitment. We also demonstrated that ovarian VEGF inhibition can partially restore the accumulation of small follicles in PCOS rats and reduces cyst formation, improving ovulation and follicular development. Therefore, the inhibition of VEGF could be considered, in addition to other currently applied treatments, as a new strategy to be studied in PCOS patients to restore ovarian function.
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angiopoietins tie2 system and vegf are involved in ovarian function in a dhea rat model of polycystic ovary syndrome
Endocrinology, 2012Co-Authors: Fernanda Parborell, Dalhia Abramovich, Griselda Irusta, Marta Tesone, Natalia I CataldiAbstract:Polycystic ovary syndrome (PCOS) is the most common endocrinological pathology among women of reproductive age. It is characterized by anovulation, oligo- or amenorrhea, hyperandrogenism, obesity, and insulin resistance. PCOS patients present with elevated levels of vascular endothelial growth factor (VEGF) in serum and follicular fluid. In this study, we examined the ovarian expression of angiopoietins (ANGPT) and their receptor tyrosine kinase receptor (TIE2), involved in the stabilization of blood vessels, in a rat model of dehydroepiandrosterone-induced PCOS. We also analyzed the effect of ovarian VEGF inhibition on ANGPT/TIE2, follicular development, and vascular stability. VEGF levels were increased in the PCOS ovaries, whereas the levels of its receptor fetal liver kinase-1 were decreased. In addition, the periendothelial cell area and the ANGPT1 to ANGPT2 ratio in the ovary were increased in the PCOS group. Percentage of primary follicles was increased and the percentage of preantral follicles and...
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angiopoietin 1 reduces rat follicular atresia mediated by apoptosis through the pi3k akt pathway
Molecular and Cellular Endocrinology, 2011Co-Authors: Fernanda Parborell, Dalhia Abramovich, Griselda Irusta, Marta TesoneAbstract:Abstract The aim of this study was to determine the effect of the local inhibition of ANGPT1 on steroid production, proliferation and apoptosis of ovarian follicular cells and on the PI3K/AKT pathway. We also examined the effect of ANGPTs on follicular cell apoptosis and proliferation in early antral follicles (EAFs) in culture. Follicular cells expressing PCNA decreased after ANGPT1 Ab treatment. Moreover, ANGPT1 inhibition increased the levels of active caspase 3 and androsterone, but decreased estradiol, AKT phosphorylation and the area of smooth muscle cell actin. In cultured EAFs from prepubertal rats treated with diethylstilbestrol (DES), ANGPT1 increased PCNA and decreased apoptosis while ANGPT2 reversed these effects. These results show that ANGPT1 alters steroidogenesis, reduces ovarian apoptosis, and stimulates cell proliferation in antral follicles. ANGPT1 may exert these roles by regulating ovarian vascular stability and/or by a direct effect on follicular cells, possibly involving the PI3K/AKT pathway.
Gou Young Koh - One of the best experts on this subject based on the ideXlab platform.
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angiopoietin 2 integrin α5β1 signaling enhances vascular fatty acid transport and prevents ectopic lipid induced insulin resistance
Nature Communications, 2020Co-Authors: Hosung Bae, Cholsoon Jang, Ki Yong Hong, Choongkun Lee, Seungjun Lee, Kibaek Choe, Stefan Offermanns, Hyuek Jong Lee, Gou Young KohAbstract:Proper storage of excessive dietary fat into subcutaneous adipose tissue (SAT) prevents ectopic lipid deposition-induced insulin resistance, yet the underlying mechanism remains unclear. Here, we identify angiopoietin-2 (ANGPT2)-integrin α5β1 signaling as an inducer of fat uptake specifically in SAT. Adipocyte-specific deletion of ANGPT2 markedly reduced fatty acid uptake and storage in SAT, leading to ectopic lipid accumulation in glucose-consuming organs including skeletal muscle and liver and to systemic insulin resistance. Mechanistically, ANGPT2 activated integrin α5β1 signaling in the endothelium and triggered fatty acid transport via CD36 and FATP3 into SAT. Genetic or pharmacological inhibition of the endothelial integrin α5β1 recapitulated adipocyte-specific ANGPT2 knockout phenotypes. Our findings demonstrate the critical roles of ANGPT2-integrin α5β1 signaling in SAT endothelium in regulating whole-body fat distribution for metabolic health and highlight adipocyte-endothelial crosstalk as a potential target for prevention of ectopic lipid deposition-induced lipotoxicity and insulin resistance.
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Angiopoietin-2–integrin α5β1 signaling enhances vascular fatty acid transport and prevents ectopic lipid-induced insulin resistance
'Springer Science and Business Media LLC', 2020Co-Authors: Hosung Bae, Cholsoon Jang, Ki Yong Hong, Choongkun Lee, Seungjun Lee, Kibaek Choe, Stefan Offermanns, Hyuek Jong Lee, Gou Young KohAbstract:© 2020, The Author(s). Proper storage of excessive dietary fat into subcutaneous adipose tissue (SAT) prevents ectopic lipid deposition-induced insulin resistance, yet the underlying mechanism remains unclear. Here, we identify angiopoietin-2 (ANGPT2)–integrin α5β1 signaling as an inducer of fat uptake specifically in SAT. Adipocyte-specific deletion of ANGPT2 markedly reduced fatty acid uptake and storage in SAT, leading to ectopic lipid accumulation in glucose-consuming organs including skeletal muscle and liver and to systemic insulin resistance. Mechanistically, ANGPT2 activated integrin α5β1 signaling in the endothelium and triggered fatty acid transport via CD36 and FATP3 into SAT. Genetic or pharmacological inhibition of the endothelial integrin α5β1 recapitulated adipocyte-specific ANGPT2 knockout phenotypes. Our findings demonstrate the critical roles of ANGPT2–integrin α5β1 signaling in SAT endothelium in regulating whole-body fat distribution for metabolic health and highlight adipocyte–endothelial crosstalk as a potential target for prevention of ectopic lipid deposition-induced lipotoxicity and insulin resistance11sci
Dalhia Abramovich - One of the best experts on this subject based on the ideXlab platform.
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metformin regulates ovarian angiogenesis and follicular development in a female polycystic ovary syndrome rat model
Endocrinology, 2015Co-Authors: Mariana Di Pietro, Fernanda Parborell, Griselda Irusta, Marta Tesone, Diana Bas, Natalia Pascuali, Maria Silvia Bianchi, Dalhia AbramovichAbstract:Polycystic ovary syndrome (PCOS) is a frequent pathology that affects more than 5% of women of reproductive age. Among other heterogeneous symptoms, PCOS is characterized by abnormalities in angiogenesis. Metformin has been introduced in the treatment of PCOS to manage insulin resistance and hyperglycemia. Besides its metabolic effects, metformin has been shown to improve ovulation, pregnancy and live birth rates in PCOS patients. In the present study, we used a dehydroepiandrosterone-induced PCOS rat model to analyze the effect of metformin administration on ovarian angiogenesis. We found that metformin was able to restore the increased levels of vascular endothelial growth factor, angiopoietin (ANGPT)1, and ANGPT1/ANGPT2 ratio and the decreased levels of platelet-derived growth factor B and platelet-derived growth factor D observed in the dehydroepiandrosterone-treated rats. These effects could take place, at least in part, through a decrease in the levels of serum insulin. We also found an improvement in follicular development, with a lower percentage of small follicles and cysts and a higher percentage of antral follicles and corpora lutea after metformin administration. The improvement in ovarian angiogenesis is likely to restore the accumulation of small follicles observed in PCOS rats and to reduce cyst formation, thus improving follicular development and the percentage of corpora lutea. These results open new insights into the study of metformin action not only in glucose metabolism but also in ovarian dysfunction in PCOS women.
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angiopoietins tie2 system and vegf are involved in ovarian function in a dhea rat model of polycystic ovary syndrome
Endocrinology, 2012Co-Authors: Fernanda Parborell, Dalhia Abramovich, Griselda Irusta, Marta Tesone, Natalia I Cataldi, Diana BasAbstract:Polycystic ovary syndrome (PCOS) is the most common endocrinological pathology among women of reproductive age. It is characterized by anovulation, oligo- or amenorrhea, hyperandrogenism, obesity, and insulin resistance. PCOS patients present with elevated levels of vascular endothelial growth factor (VEGF) in serum and follicular fluid. In this study, we examined the ovarian expression of angiopoietins (ANGPT) and their receptor tyrosine kinase receptor (TIE2), involved in the stabilization of blood vessels, in a rat model of dehydroepiandrosterone-induced PCOS. We also analyzed the effect of ovarian VEGF inhibition on ANGPT/TIE2, follicular development, and vascular stability. VEGF levels were increased in the PCOS ovaries, whereas the levels of its receptor fetal liver kinase-1 were decreased. In addition, the periendothelial cell area and the ANGPT1 to ANGPT2 ratio in the ovary were increased in the PCOS group. Percentage of primary follicles was increased and the percentage of preantral follicles and corpora lutea was decreased in the PCOS group. VEGF inhibition decreased the percentage of primary follicles close to control values. Interestingly, despite the presence of cysts in the ovaries from VEGF inhibitor-treated PCOS rats, its percentage was lower than the PCOS group without treatment. In summary, this study describes an alteration not only in the VEGF/fetal liver kinase-1 system but also in the ANGPT/TIE2 system in a dehydroepiandrosterone-induced PCOS rat model. This leads to an increase in periendothelial cell recruitment. We also demonstrated that ovarian VEGF inhibition can partially restore the accumulation of small follicles in PCOS rats and reduces cyst formation, improving ovulation and follicular development. Therefore, the inhibition of VEGF could be considered, in addition to other currently applied treatments, as a new strategy to be studied in PCOS patients to restore ovarian function.
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angiopoietins tie2 system and vegf are involved in ovarian function in a dhea rat model of polycystic ovary syndrome
Endocrinology, 2012Co-Authors: Fernanda Parborell, Dalhia Abramovich, Griselda Irusta, Marta Tesone, Natalia I CataldiAbstract:Polycystic ovary syndrome (PCOS) is the most common endocrinological pathology among women of reproductive age. It is characterized by anovulation, oligo- or amenorrhea, hyperandrogenism, obesity, and insulin resistance. PCOS patients present with elevated levels of vascular endothelial growth factor (VEGF) in serum and follicular fluid. In this study, we examined the ovarian expression of angiopoietins (ANGPT) and their receptor tyrosine kinase receptor (TIE2), involved in the stabilization of blood vessels, in a rat model of dehydroepiandrosterone-induced PCOS. We also analyzed the effect of ovarian VEGF inhibition on ANGPT/TIE2, follicular development, and vascular stability. VEGF levels were increased in the PCOS ovaries, whereas the levels of its receptor fetal liver kinase-1 were decreased. In addition, the periendothelial cell area and the ANGPT1 to ANGPT2 ratio in the ovary were increased in the PCOS group. Percentage of primary follicles was increased and the percentage of preantral follicles and...
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angiopoietin 1 reduces rat follicular atresia mediated by apoptosis through the pi3k akt pathway
Molecular and Cellular Endocrinology, 2011Co-Authors: Fernanda Parborell, Dalhia Abramovich, Griselda Irusta, Marta TesoneAbstract:Abstract The aim of this study was to determine the effect of the local inhibition of ANGPT1 on steroid production, proliferation and apoptosis of ovarian follicular cells and on the PI3K/AKT pathway. We also examined the effect of ANGPTs on follicular cell apoptosis and proliferation in early antral follicles (EAFs) in culture. Follicular cells expressing PCNA decreased after ANGPT1 Ab treatment. Moreover, ANGPT1 inhibition increased the levels of active caspase 3 and androsterone, but decreased estradiol, AKT phosphorylation and the area of smooth muscle cell actin. In cultured EAFs from prepubertal rats treated with diethylstilbestrol (DES), ANGPT1 increased PCNA and decreased apoptosis while ANGPT2 reversed these effects. These results show that ANGPT1 alters steroidogenesis, reduces ovarian apoptosis, and stimulates cell proliferation in antral follicles. ANGPT1 may exert these roles by regulating ovarian vascular stability and/or by a direct effect on follicular cells, possibly involving the PI3K/AKT pathway.
Dirk J Duncker - One of the best experts on this subject based on the ideXlab platform.
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Endothelial loss of Fzd5 stimulates PKC/Ets1-mediated transcription of ANGPT2 and Flt1
Angiogenesis, 2018Co-Authors: Maarten M. Brandt, Christian G. M. Dijk, Ihsan Chrifi, Heleen M. Kool, Petra E. Bürgisser, Laura Louzao-martinez, Jiayi Pei, Robbert J Rottier, Marianne C. Verhaar, Dirk J DunckerAbstract:AimsFormation of a functional vascular system is essential and its formation is a highly regulated process initiated during embryogenesis, which continues to play important roles throughout life in both health and disease. In previous studies, Fzd5 was shown to be critically involved in this process and here we investigated the molecular mechanism by which endothelial loss of this receptor attenuates angiogenesis.Methods and resultsUsing short interference RNA-mediated loss-of-function assays, the function and mechanism of signaling via Fzd5 was studied in human endothelial cells (ECs). Our findings indicate that Fzd5 signaling promotes neovessel formation in vitro in a collagen matrix-based 3D co-culture of primary vascular cells. Silencing of Fzd5 reduced EC proliferation, as a result of G0/G1 cell cycle arrest, and decreased cell migration. Furthermore, Fzd5 knockdown resulted in enhanced expression of the factors ANGPT2 and Flt1, which are mainly known for their destabilizing effects on the vasculature. In Fzd5-silenced ECs, ANGPT2 and Flt1 upregulation was induced by enhanced PKC signaling, without the involvement of canonical Wnt signaling, non-canonical Wnt/Ca2+-mediated activation of NFAT, and non-canonical Wnt/PCP-mediated activation of JNK. We demonstrated that PKC-induced transcription of ANGPT2 and Flt1 involved the transcription factor Ets1.ConclusionsThe current study demonstrates a pro-angiogenic role of Fzd5, which was shown to be involved in endothelial tubule formation, cell cycle progression and migration, and partly does so by repression of PKC/Ets1-mediated transcription of Flt1 and ANGPT2.
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endothelial loss of fzd5 stimulates pkc ets1 mediated transcription of ANGPT2 and flt1
Angiogenesis, 2018Co-Authors: Maarten M. Brandt, Ihsan Chrifi, Heleen M. Kool, Petra E. Bürgisser, Jiayi Pei, Robbert J Rottier, Marianne C. Verhaar, Christian G M Van Dijk, Laura Louzaomartinez, Dirk J DunckerAbstract:Aims: Formation of a functional vascular system is essential and its formation is a highly regulated process initiated during embryogenesis, which continues to play important roles throughout life in both health and disease. In previous studies, Fzd5 was shown to be critically involved in this process and here we investigated the molecular mechanism by which endothelial loss of this receptor attenuates angiogenesis. Methods and results: Using short interference RNA-mediated loss-of-function assays, the function and mechanism of signaling via Fzd5 was studied in human endothelial cells (ECs). Our findings indicate that Fzd5 signaling promotes neovessel formation in vitro in a collagen matrix-based 3D co-culture of primary vascular cells. Silencing of Fzd5 reduced EC proliferation, as a result of G0/G1 cell cycle arrest, and decreased cell migration. Furthermore, Fzd5 knockdown resulted in enhanced expression of the factors ANGPT2 and Flt1, which are mainly known for their destabilizing effects on the vasculature. In Fzd5-silenced ECs, ANGPT2 and Flt1 upregulation was induced by enhanced PKC signaling, without the involvement of canonical Wnt signaling, non-canonical Wnt/Ca2+-mediated activation of NFAT, and non-canonical Wnt/PCP-mediated activation of JNK. We demonstrated that PKC-induced transcription of ANGPT2 and Flt1 involved the transcription factor Ets1. Conclusions: The current study demonstrates a pro-angiogenic role of Fzd5, which was shown to be involved in endothelial tubule formation, cell cycle progression and migration, and partly does so by repression of PKC/Ets1-mediated transcription of Flt1 and ANGPT2.
Hosung Bae - One of the best experts on this subject based on the ideXlab platform.
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angiopoietin 2 integrin α5β1 signaling enhances vascular fatty acid transport and prevents ectopic lipid induced insulin resistance
Nature Communications, 2020Co-Authors: Hosung Bae, Cholsoon Jang, Ki Yong Hong, Choongkun Lee, Seungjun Lee, Kibaek Choe, Stefan Offermanns, Hyuek Jong Lee, Gou Young KohAbstract:Proper storage of excessive dietary fat into subcutaneous adipose tissue (SAT) prevents ectopic lipid deposition-induced insulin resistance, yet the underlying mechanism remains unclear. Here, we identify angiopoietin-2 (ANGPT2)-integrin α5β1 signaling as an inducer of fat uptake specifically in SAT. Adipocyte-specific deletion of ANGPT2 markedly reduced fatty acid uptake and storage in SAT, leading to ectopic lipid accumulation in glucose-consuming organs including skeletal muscle and liver and to systemic insulin resistance. Mechanistically, ANGPT2 activated integrin α5β1 signaling in the endothelium and triggered fatty acid transport via CD36 and FATP3 into SAT. Genetic or pharmacological inhibition of the endothelial integrin α5β1 recapitulated adipocyte-specific ANGPT2 knockout phenotypes. Our findings demonstrate the critical roles of ANGPT2-integrin α5β1 signaling in SAT endothelium in regulating whole-body fat distribution for metabolic health and highlight adipocyte-endothelial crosstalk as a potential target for prevention of ectopic lipid deposition-induced lipotoxicity and insulin resistance.
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Angiopoietin-2–integrin α5β1 signaling enhances vascular fatty acid transport and prevents ectopic lipid-induced insulin resistance
'Springer Science and Business Media LLC', 2020Co-Authors: Hosung Bae, Cholsoon Jang, Ki Yong Hong, Choongkun Lee, Seungjun Lee, Kibaek Choe, Stefan Offermanns, Hyuek Jong Lee, Gou Young KohAbstract:© 2020, The Author(s). Proper storage of excessive dietary fat into subcutaneous adipose tissue (SAT) prevents ectopic lipid deposition-induced insulin resistance, yet the underlying mechanism remains unclear. Here, we identify angiopoietin-2 (ANGPT2)–integrin α5β1 signaling as an inducer of fat uptake specifically in SAT. Adipocyte-specific deletion of ANGPT2 markedly reduced fatty acid uptake and storage in SAT, leading to ectopic lipid accumulation in glucose-consuming organs including skeletal muscle and liver and to systemic insulin resistance. Mechanistically, ANGPT2 activated integrin α5β1 signaling in the endothelium and triggered fatty acid transport via CD36 and FATP3 into SAT. Genetic or pharmacological inhibition of the endothelial integrin α5β1 recapitulated adipocyte-specific ANGPT2 knockout phenotypes. Our findings demonstrate the critical roles of ANGPT2–integrin α5β1 signaling in SAT endothelium in regulating whole-body fat distribution for metabolic health and highlight adipocyte–endothelial crosstalk as a potential target for prevention of ectopic lipid deposition-induced lipotoxicity and insulin resistance11sci
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Impaired angiopoietin/Tie2 signaling compromises Schlemm's canal integrity and induces glaucoma
'American Society for Clinical Investigation', 2018Co-Authors: Jaeryung Kim, Hosung Bae, Choongkun Lee, Dae-young Park, Do Young Park, Dongkyu Kim, Sukhyun Song, Tae-young Chung, Dong Hui Lim, Yoshiaki KubotaAbstract:Primary open-angle glaucoma (POAG) is often caused by elevated intraocular pressure (IOP), which arises due to increased resistance to aqueous humor outflow (AHO). Aqueous humor flows through Schlemm's canal (SC), a lymphatic-like vessel encircling the cornea, and via intercellular spaces of ciliary muscle cells. However, the mechanisms underlying increased AHO resistance are poorly understood. Here, we demonstrate that signaling between angiopoietin (Angpt) and the Angpt receptor Tie2, which is critical for SC formation, is also indispensable for maintaining SC integrity during adulthood. Deletion of Angpt1/ANGPT2 or Tie2 in adult mice severely impaired SC integrity and transcytosis, leading to elevated IOP, retinal neuron damage, and impairment of retinal ganglion cell function, all hallmarks of POAG in humans. We found that SC integrity is maintained by interconnected and coordinated functions of Angpt-Tie2 signaling, AHO, and Prox1 activity. These functions diminish in the SC during aging, leading to impaired integrity and transcytosis. Intriguingly, Tie2 reactivation using a Tie2 agonistic antibody rescued the POAG phenotype in Angpt1/ANGPT2-deficient mice and rejuvenated the SC in aged mice. These results indicate that the Angpt-Tie2 system is essential for SC integrity. The impairment of this system underlies POAG-associated pathogenesis, supporting the possibility that Tie2 agonists could be a therapeutic option for glaucoma.
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Angiopoietin-2 exacerbates cardiac hypoxia and inflammation after myocardial infarction
AMER SOC CLINICAL INVESTIGATION INC, 2018Co-Authors: Seungjun Lee, Hosung Bae, Choongkun Lee, Seok Kang, Intae Park, Yoo Hyung Kim, Seo Ki Kim, Seon Pyo Hong, Yoshiaki KubotaAbstract:Emerging evidence indicates that angiopoietin-2 (ANGPT2), a well-recognized vascular destabilizing factor, is a biomarker of poor outcome in ischemic heart disease. However, its precise role in postischemic cardiovascular remodeling is poorly understood. Here, we show that ANGPT2 plays multifaceted roles in the exacerbation of cardiac hypoxia and inflammation after myocardial ischemia. ANGPT2 was highly expressed in endothelial cells at the infarct border zone after myocardial infarction (MI) or ischemia/reperfusion injury in mice. In the acute phase of MI, endothelial-derived ANGPT2 antagonized Angpt1/Tie2 signaling, which was greatly involved in pericyte detachment, vascular leakage, increased adhesion molecular expression, degradation of the glycocalyx and extracellular matrix, and enhanced neutrophil infiltration and hypoxia in the infarct border area. In the chronic remodeling phase after MI, endothelial- and macrophage-derived ANGPT2 continuously promoted abnormal vascular remodeling and proinflammatory macrophage polarization through integrin ��5��1 signaling, worsening cardiac hypoxia and inflammation. Accordingly, inhibition of ANGPT2 either by gene deletion or using an anti-ANGPT2 blocking antibody substantially alleviated these pathological findings and ameliorated postischemic cardiovascular remodeling. Blockade of ANGPT2 thus has potential as a therapeutic option for ischemic heart failur
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impaired angiopoietin tie2 signaling compromises schlemm s canal integrity and induces glaucoma
Journal of Clinical Investigation, 2017Co-Authors: Jaeryung Kim, Hosung Bae, Choongkun Lee, Dae-young Park, Do Young Park, Dongkyu Kim, Sukhyun Song, Tae-young Chung, Dong Hui LimAbstract:Primary open-angle glaucoma (POAG) is often caused by elevated intraocular pressure (IOP), which arises due to increased resistance to aqueous humor outflow (AHO). Aqueous humor flows through Schlemm's canal (SC), a lymphatic-like vessel encircling the cornea, and via intercellular spaces of ciliary muscle cells. However, the mechanisms underlying increased AHO resistance are poorly understood. Here, we demonstrate that signaling between angiopoietin (Angpt) and the Angpt receptor Tie2, which is critical for SC formation, is also indispensable for maintaining SC integrity during adulthood. Deletion of Angpt1/ANGPT2 or Tie2 in adult mice severely impaired SC integrity and transcytosis, leading to elevated IOP, retinal neuron damage, and impairment of retinal ganglion cell function, all hallmarks of POAG in humans. We found that SC integrity is maintained by interconnected and coordinated functions of Angpt-Tie2 signaling, AHO, and Prox1 activity. These functions diminish in the SC during aging, leading to impaired integrity and transcytosis. Intriguingly, Tie2 reactivation using a Tie2 agonistic antibody rescued the POAG phenotype in Angpt1/ANGPT2-deficient mice and rejuvenated the SC in aged mice. These results indicate that the Angpt-Tie2 system is essential for SC integrity. The impairment of this system underlies POAG-associated pathogenesis, supporting the possibility that Tie2 agonists could be a therapeutic option for glaucoma.