The Experts below are selected from a list of 22080 Experts worldwide ranked by ideXlab platform
Sudarshan Anand - One of the best experts on this subject based on the ideXlab platform.
-
microrna regulation of the mrn complex impacts dna damage cellular senescence and angiogenic Signaling
Cell Death and Disease, 2018Co-Authors: Cristina Espinosadiez, Raeanna Wilson, Namita Chatterjee, Clayton Hudson, Rebecca Ruhl, Christina Hipfinger, Erin Helms, Omar F. Khan, Daniel G. Anderson, Sudarshan AnandAbstract:MicroRNAs (miRs) contribute to biological robustness by buffering cellular processes from external perturbations. Here we report an unexpected link between DNA damage response and angiogenic Signaling that is buffered by a miR. We demonstrate that genotoxic stress-induced miR-494 inhibits the DNA repair machinery by targeting the MRE11a-RAD50-NBN (MRN) complex. Gain- and loss-of-function experiments show that miR-494 exacerbates DNA damage and drives endothelial senescence. Increase of miR-494 affects telomerase activity, activates p21, decreases pRb pathways, and diminishes angiogenic sprouting. Genetic and pharmacological disruption of the MRN pathway decreases VEGF Signaling, phenocopies miR-494-induced senescence, and disrupts angiogenic sprouting. Vascular-targeted delivery of miR-494 decreases both growth factor-induced and tumor angiogenesis in mouse models. Our work identifies a putative miR-facilitated mechanism by which endothelial cells can be insulated against VEGF Signaling to facilitate the onset of senescence and highlight the potential of targeting DNA repair to disrupt pathological angiogenesis.
-
microrna regulation of the mrn complex impacts dna damage cellular senescence and angiogenic Signaling
bioRxiv, 2018Co-Authors: Cristina Espinosadiez, Raeanna Wilson, Namita Chatterjee, Clayton Hudson, Rebecca Ruhl, Christina Hipfinger, Erin Helms, Omar F. Khan, Daniel G. Anderson, Sudarshan AnandAbstract:MicroRNAs contribute to biological robustness by buffering cellular processes from external perturbations. Here we report an unexpected link between DNA damage response and angiogenic Signaling that is buffered by two distinct microRNAs. We demonstrate that genotoxic stress-induced miR-494 and miR-99b inhibit the DNA repair machinery by targeting the MRE11a-RAD50-NBN (MRN) complex. Functionally, gain and loss of function experiments show that miR-494 and miR-99b affect telomerase activity, activate p21 and Rb pathways and diminish angiogenic sprouting in vitro and in vivo. Genetic and pharmacological disruption of VEGFR-2 Signaling and the MRN complex reveal a surprising co-dependency of these pathways in regulating endothelial senescence and proliferation. Vascular-targeted delivery of miR-494 decreases both growth factor -induced and tumor angiogenesis in mouse models. Mechanistically, disruption of the MRN complex induced CD44, a known driver of senescence and regulator of VEGF Signaling in addition to suppressing IL-13 a stimulator of VEGF Signaling. Our work identifies a putative miR-facilitated mechanism by which endothelial cells can be insulated against VEGF Signaling to facilitate the onset of senescence and highlight the potential of targeting DNA repair to disrupt pathological angiogenesis.
-
MicroRNA perturbation of the MRN complex buffers DNA damage response from VEGF Signaling
2017Co-Authors: Cristina Espinosa-diez, Raeanna Wilson, Namita Chatterjee, Clayton Hudson, Rebecca Ruhl, Christina Hipfinger, Erin Helms, Omar F. Khan, Daniel G. Anderson, Sudarshan AnandAbstract:MicroRNAs contribute to biological robustness by buffering cellular processes from external perturbations. Here we report an unexpected link between DNA damage response and angiogenic Signaling that is buffered by two distinct microRNAs. We demonstrate that genotoxic stress-induced miR-494 and miR-99b inhibit the DNA repair machinery by targeting the MRE11a-RAD50-NBN (MRN) complex. Functionally, miR-494 and miR-99b affect telomerase activity, activate p21 and Rb pathways and diminish angiogenic sprouting in vitro and in vivo. Genetic and pharmacological disruption of VEGFR-2 Signaling and the MRN complex reveal a surprising co-dependency of these pathways in regulating endothelial senescence and proliferation. miR-99b diminishes VEGF Signaling, transcriptional responses and proliferation. Disruption of the MRN complex induces CD44, a known driver of senescence and regulator of VEGF Signaling. Our work identifies a putative miR-facilitated mechanism by which endothelial cells can be insulated against VEGF Signaling to facilitate the onset of senescence.
Dongmei Fan - One of the best experts on this subject based on the ideXlab platform.
-
microrna 183 suppresses neuropathic pain and expression of ampa receptors by targeting mtor VEGF Signaling pathway
Cellular Physiology and Biochemistry, 2017Co-Authors: Xiaojuan Xie, Wei Zhang, Dongmei FanAbstract:Background: Neuropathic pain is a type of chronic pain that results from dysfunctions of the somatosensory nerve system. This study was aimed to investigate the effect of mTOR/VEGF Signaling pathway on neuropathic pain and the regulation mechanisms of miR-183 on AMPA Receptors through mTOR/VEGF Signaling pathway. Methods: Chronic compress injury (CCI) model was constructed in the current study, we used paw withdrawal mechanic threshold (PWMT) and paw withdrawal thermal latency (PWTL) to observe mTOR and VEGF receptors. Dual luciferase analysis, western blot and qRT-PCR were also applied to complete this experiment. Results: It was observed that the inhibition of mTOR and VEGF receptors could significantly relieve neuropathic pain in the CCI model. Moreover mTOR was confirmed as the direct target of miR-183. Furthermore, miR-183 could modulate VEGF through regulating mTOR expressions. We also found the expressions of AMPA receptors (i.e. GluR1 and GluR2), located in the downstream of mTOR/VEGF Signaling pathway, were significantly upregulated when miR-183 was downregulated or when the mTOR/VEGF Signaling pathway was activated. Conclusion: The inhibition of mTOR or VEGF receptors can significantly relieve neuropathic pain, and the upregulation of miR-183 can suppress AMPA receptors by inhibiting mTOR/VEGF pathway.
-
MicroRNA-183 Suppresses Neuropathic Pain and Expression of AMPA Receptors by Targeting mTOR/VEGF Signaling Pathway
Karger Publishers, 2017Co-Authors: Xiaojuan Xie, Wei Zhang, Dongmei FanAbstract:Background: Neuropathic pain is a type of chronic pain that results from dysfunctions of the somatosensory nerve system. This study was aimed to investigate the effect of mTOR/VEGF Signaling pathway on neuropathic pain and the regulation mechanisms of miR-183 on AMPA Receptors through mTOR/VEGF Signaling pathway. Methods: Chronic compress injury (CCI) model was constructed in the current study, we used paw withdrawal mechanic threshold (PWMT) and paw withdrawal thermal latency (PWTL) to observe mTOR and VEGF receptors. Dual luciferase analysis, western blot and qRT-PCR were also applied to complete this experiment. Results: It was observed that the inhibition of mTOR and VEGF receptors could significantly relieve neuropathic pain in the CCI model. Moreover mTOR was confirmed as the direct target of miR-183. Furthermore, miR-183 could modulate VEGF through regulating mTOR expressions. We also found the expressions of AMPA receptors (i.e. GluR1 and GluR2), located in the downstream of mTOR/VEGF Signaling pathway, were significantly upregulated when miR-183 was downregulated or when the mTOR/VEGF Signaling pathway was activated. Conclusion: The inhibition of mTOR or VEGF receptors can significantly relieve neuropathic pain, and the upregulation of miR-183 can suppress AMPA receptors by inhibiting mTOR/VEGF pathway
Sui Peng - One of the best experts on this subject based on the ideXlab platform.
-
autocrine VEGF Signaling promotes cell proliferation through a plc dependent pathway and modulates apatinib treatment efficacy in gastric cancer
Oncotarget, 2017Co-Authors: Yi Lin, Sui Peng, Zhirong Zeng, Ertao Zhai, Bing Liao, Xinhua Zhang, Shirong Cai, Minhu ChenAbstract:// Yi Lin 1, * , Ertao Zhai 2, * , Bing Liao 3, * , Lixia Xu 1 , Xinhua Zhang 2 , Sui Peng 1 , Yulong He 2 , Shirong Cai 2 , Zhirong Zeng 1 , Minhu Chen 1 1 Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P.R.China 2 Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P.R.China 3 Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P.R.China * These authors have contributed equally to this work Correspondence to: Shirong Cai, email: caisrteam@163.com Zhirong Zeng, email: zengzhirong@vip.163.com Keywords: autocrine, VEGF, proliferation, Apatinib, gastric cancer Received: December 16, 2015 Accepted: December 25, 2016 Published: January 03, 2017 ABSTRACT Background: Tumor cells produce vascular endothelial growth factor (VEGF) which interact with the membrane or cytoplasmic VEGF receptors (VEGFRs) to promote cell growth in an angiogenesis-independent fashion. Apatinib, a highly selective VEGFR2 inhibitor, is the only effective drug for patients with terminal gastric cancer (GC) who have no other chemotherapeutic options. However, its treatment efficacy is still controversy and the mechanism behind remains undetermined. In this study, we aimed to investigate the role of autocrine VEGF Signaling in the growth of gastric cancer cells and the efficacy of Apatinib treatment. Methods: The expression of phosphor VEGFR2 in gastric cancer cell lines was determined by real-time PCR, immunofluorescence, and Western blot. The gastric cancer cells were administrated with or without recombination human VEGF (rhVEGF), VEGFR2 neutralizing antibody, U73122, SU1498, and Apatinib. The nude mice were used for xenograft tumor model. Results: we found that autocrine VEGF induced high VEGFR2-expression, promoted phosphorylation of VEGFR2, and further enhanced internalization of pVEGFR2 in gastric cancer cells. The autocrine VEGF was self-sustained through increasing VEGF mRNA and protein expression. It exerted pro-proliferative effect through a PLC-ERK1/2 dependent pathway. Furthermore, we demonstrated that in VEGFR2 overexpressing gastric cancer cells, Apatinib inhibited cell proliferation in vitro and delayed xenograft tumor growth in vivo . However, these effects were not observed in VEGFR2 low expressing gastric cancer cells. Conclusion: These results suggested that autocrine VEGF Signaling promotes gastric cancer cell proliferation and enhances Apatinib treatment outcome in VEGFR2 overexpression gastric cancer cells both in vitro and in vivo . This study would enable better stratification of gastric cancer patients for clinical treatment decision.
-
intracellular autocrine VEGF Signaling promotes ebdc cell proliferation which can be inhibited by apatinib
Cancer Letters, 2016Co-Authors: Sui Peng, Qiuyang Zhang, Yanyan Zhang, Hong Peng, Allan Tsung, Samer Tohme, Hai Huang, Riccardo Lencioni, Zhirong Zeng, Baogang PengAbstract:Tumor cells produce vascular endothelial growth factor (VEGF) which can interact with membrane or cytoplasmic VEGF receptors (VEGFRs) to promote cell growth. We aimed to investigate the role of extracellular/intracellular autocrine VEGF Signaling and Apatinib, a highly selective VEGFR2 inhibitor, in extrahepatic bile duct cancer (EBDC). We found conditioned medium or recombinant human VEGF treatment promoted EBDC cell proliferation through a phospholipase C-γ1-dependent pathway. This pro-proliferative effect was diminished by VEGF, VEGFR1 or VEGFR2 neutralizing antibodies, but more significantly suppressed by intracellular VEGFR inhibitor. The rhVEGF induced intracellular VEGF Signaling by promoting nuclear accumulation of pVEGFR1/2 and enhancing VEGF promoter activity, mRNA and protein expression. Internal VEGFR2 inhibitor Apatinib significantly inhibited intracellular VEGF Signaling, suppressed cell proliferation in vitro and delayed xenograft tumor growth in vivo, while anti-VEGF antibody Bevacizumab showed no effect. Clinically, overexpression of pVEGFR1 and pVEGFR2 was significantly correlated with poorer overall survival (P = .007 and P = .020, respectively). In conclusion, the intracellular autocrine VEGF loop plays a predominant role in VEGF-induced cell proliferation. Apatinib is an effective intracellular VEGF pathway blocker that presents a great therapeutic potential in EBDC.
-
apatinib inhibits VEGF Signaling and promotes apoptosis in intrahepatic cholangiocarcinoma
Oncotarget, 2016Co-Authors: Hong Peng, Qiuyang Zhang, Baogang Peng, Ning Zhang, Yunpeng Hua, Yubin Deng, Jiaming Lai, Zhenwei Peng, Minhu Chen, Sui PengAbstract:Tumor cells co-express vascular endothelial growth factor (VEGF) and VEGF receptors (VEGFRs) that interact each other to support a self-sustainable cell growth. So far, this autocrine VEGF loop is not reported in human intrahepatic cholangiocarcinoma (ICC). Apatinib is a highly selective VEGFR2 inhibitor, but its effects on ICC have not been investigated. In this study, we reported that VEGF and phosphorylated VEGFR2 were expressed at a significantly high level in ICC patient tissues (P<0.05). In vitro, treating ICC cell lines RBE and SSP25 with recombinant human VEGF (rhVEGF) induced phosphorylation of VEGFR1 (pVEGFR1) and VEGFR2 (pVEGFR2); however, only the VEGFR2 played a role in the anti-apoptotic cell growth through activating a PI3K-AKT-mTOR anti-apoptotic Signaling pathway which generated more VEGF to enter this autocrine loop. Apatinib inhibited the anti-apoptosis induced by VEGF Signaling, and promoted cell death in vitro. In addition, Apatinib treatment delayed xenograft tumor growth in vivo. In conclusion, the autocrine VEGF/VEGFR2 Signaling promotes ICC cell survival. Apatinib inhibits anti-apoptotic cell growth through suppressing the autocrine VEGF Signaling, supporting a potential role for using Apatinib in the treatment of ICC.
-
autocrine vascular endothelial growth factor Signaling promotes cell proliferation and modulates sorafenib treatment efficacy in hepatocellular carcinoma
Hepatology, 2014Co-Authors: Sui Peng, Hong Peng, Riccardo Lencioni, Baogang Peng, Minhu Chen, Ye Wang, Dong Chen, Shunli Shen, Ming KuangAbstract:Tumor cells express vascular endothelial growth factor (VEGF) that can activate VEGF receptors (VEGFRs) on or within tumor cells to promote growth in an angiogenesis-independent fashion; however, this autocrine VEGF pathway has not been reported in hepatocellular carcinoma (HCC). Sorafenib, an angiogenic inhibitor, is the only drug approved for use in advanced HCC patients. Yet the treatment efficacy is diverse and the mechanism behind it remains undetermined. Our aims were to study the molecular mechanisms underlying autocrine VEGF Signaling in HCC cells and evaluate the critical role of autocrine VEGF Signaling on sorafenib treatment efficacy. By immunohistochemistry, we found robust nuclear and cytoplasmic staining for active, phosphorylated VEGF receptor 1 (pVEGFR1) and phosphorylated VEGF receptor 2 (pVEGFR2), and by western blotting we found that membrane VEGFR1 and VEGFR2 increased in HCC tissues. We showed that autocrine VEGF promoted phosphorylation of VEGFR1 and VEGFR2 and internalization of pVEGFR2 in HCC cells, which was both pro-proliferative through a protein lipase C-extracellular kinase pathway and self-sustaining through increasing VEGF, VEGFR1, and VEGFR2 mRNA expressions. In high VEGFR1/2-expressing HepG2 cells, sorafenib treatment inhibited cell proliferation, reduced VEGFR2 mRNA expression in vitro, and delayed xenograft tumor growth in vivo. These results were not found in low VEGFR1/2-expressing Hep3B cells. In an advanced HCC population on sorafenib treatment for postoperative recurrence, we found that the absence of VEGFR1 or VEGFR2 expression in resected tumor tissues before sorafenib treatment was associated with poorer overall survival. Conclusion: Autocrine VEGF Signaling directly promotes HCC cell proliferation and affects the sorafenib treatment outcome in vitro and in vivo, which may enable better stratification for clinical treatment decisions. (Hepatology 2014;60:1264–1277)
-
autocrine VEGF Signaling promotes proliferation of neoplastic barrett s epithelial cells through a plc dependent pathway
Gastroenterology, 2014Co-Authors: Qiuyang Zhang, Sui Peng, Ellen Wright, Xi Zhang, Xiaofang Huo, Edaire Cheng, Thai H Pham, Kiyotaka AsanumaAbstract:Background & Aims Tumor cells express vascular endothelial growth factor (VEGF), which induces angiogenesis. VEGF also activates VEGF receptors (VEGFRs) on or within tumor cells to promote their proliferation in an autocrine fashion. We studied the mechanisms of autocrine VEGF Signaling in Barrett's esophagus cells. Methods Using Barrett's epithelial cell lines, we measured VEGF and VEGFR messenger RNA and protein, and studied the effects of VEGF Signaling on cell proliferation and VEGF secretion. We studied the effects of inhibiting factors in this pathway on levels of phosphorylated phospholipase Cγ1 (PLCG1), protein kinase C, and extracellular signal-regulated kinases (ERK)1/2. We performed immunohistochemical analysis of phosphorylated VEGFR2 on esophageal adenocarcinoma tissues. We studied effects of sunitinib, a VEGFR2 inhibitor, on proliferation of neoplastic cells and growth of xenograft tumors in mice. Results Neoplastic and non-neoplastic Barrett's cells expressed VEGF and VEGFR2 messenger RNA and protein, with higher levels in neoplastic cells. Incubation with recombinant human VEGF significantly increased secretion of VEGF protein and cell number; knockdown of PLCG1 markedly reduced the recombinant human VEGF-stimulated increase in levels of phosphorylated PLCG1 and phosphorylated ERK1/2 in neoplastic cells. Esophageal adenocarcinoma tissues showed immunostaining for phosphorylated VEGFR2. Sunitinib inhibited VEGF Signaling in neoplastic cells and reduced weight and volume of xenograft tumors in mice. Conclusions Neoplastic and non-neoplastic Barrett's epithelial cells have autocrine VEGF Signaling. In neoplastic Barrett's cells, VEGF activation of VEGFR2 initiates a PLCG1−protein kinase C−ERK pathway that promotes proliferation and is self-sustaining (by causing more VEGF production). Strategies to reduce autocrine VEGF Signaling (eg, with sunitinib) might be used to prevent or treat cancer in patients with Barrett's esophagus.
Zhirong Zhang - One of the best experts on this subject based on the ideXlab platform.
-
inhibition of hypoxia induced retinal angiogenesis by specnuezhenide an effective constituent of ligustrum lucidum ait through suppression of the hif 1α VEGF Signaling pathway
Molecules, 2016Co-Authors: Xiaoping Gao, Hongcheng Zhang, Wei Wang, Manxi Zhao, Xiaofeng Hao, Zhirong ZhangAbstract:Specnuezhenide (SPN), one of the main ingredients of Chinese medicine “Nu-zhen-zi”, has anti-angiogenic and vision improvement effects. However, studies of its effect on retinal neovascularization are limited so far. In the present study, we established a vascular endothelial growth factor A (VEGFA) secretion model of human acute retinal pigment epithelial-19 (ARPE-19) cells by exposure of 150 μM CoCl2 to the cells and determined the VEGFA concentrations, the mRNA expressions of VEGFA, hypoxia inducible factor-1α (HIF-1α) & prolyl hydroxylases 2 (PHD-2), and the protein expressions of HIF-1α and PHD-2 after treatment of 3-(5′-hydroxymethyl-2′-furyl)-1-benzylindazole (YC-1, 1.0 μg/mL) or SPN (0.2, 1.0 and 5.0 μg/mL). Furthermore, rat pups with retinopathy were treated with SPN (5.0 and 10.0 mg/kg) in an 80% oxygen atmosphere and the retinal avascular areas were assessed through visualization using infusion of ADPase and H&E stains. The results showed that SPN inhibited VEGFA secretion by ARPE-19 cells under hypoxia condition, down-regulated the mRNA expressions of VEGFA and PHD-2 slightly, and the protein expressions of VEGFA, HIF-1α and PHD-2 significantly in vitro. SPN also prevented hypoxia-induced retinal neovascularization in a rat model of oxygen-induced retinopathy in vivo. These results indicate that SPN ameliorates retinal neovascularization through inhibition of HIF-1α/VEGF Signaling pathway. Therefore, SPN has the potential to be developed as an agent for the prevention and treatment of diabetic retinopathy.
-
formononetin an active compound of astragalus membranaceus fisch bunge inhibits hypoxia induced retinal neovascularization via the hif 1α VEGF Signaling pathway
Drug Design Development and Therapy, 2016Co-Authors: Wei Wang, Xiaoping Gao, Hongcheng Zhang, Manxi Zhao, Xiaofeng Hao, Zhirong ZhangAbstract:BACKGROUND It has been reported that formononetin (FMN), one of the main ingredients from famous traditional Chinese medicine "Huang-qi" (Astragalus membranaceus [Fisch] Bunge) for Qi-tonifying, exhibits the effects of immunomodulation and tumor growth inhibition via antiangiogenesis. Furthermore, A. membranaceus may alleviate the retinal neovascularization (NV) of diabetic retinopathy. However, the information of FMN on retinal NV is limited so far. In the present study, we investigated the effects of FMN on the hypoxia-induced retinal NV and the possible related mechanisms. MATERIALS AND METHODS The VEGF secretion model of acute retinal pigment epithelial-19 (ARPE-19) cells under chemical hypoxia was established by the exposure of cells to 150 μM CoCl2 and then cells were treated with 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1, a potent HIF-1α inhibitor, 1.0 μg/mL) or different concentrations of FMN (0.2 μg/mL, 1.0 μg/mL, and 5.0 μg/mL). The supernatants of cells were collected 48 hours later to measure the VEGF concentrations, following the manufacturer's instruction. The mRNA expressions of VEGF, HIF-1α, PHD-2, and β-actin were analyzed by quantitative reverse transcription polymerase chain reaction, and the protein expressions of HIF-1α and PHD-2 were determined by Western blot analysis. Furthermore, the rats with retinopathy were treated by intraperitoneal administration of conbercept injection (1.0 mg/kg) or FMN (5.0 mg/kg and 10.0 mg/kg) in an 80% oxygen atmosphere. The retinal avascular areas were assessed through visualization of the retinal vasculature by adenosine diphosphatase staining and hematoxylin and eosin staining. RESULTS FMN can indeed inhibit the VEGF secretion of ARPE-19 cells under hypoxia, downregulate the mRNA expression of VEGFA and PHD-2, and decrease the protein expression of VEGF, HIF-1α, and PHD-2 in vitro. Furthermore, FMN can prevent hypoxia-induced retinal NV in vivo. CONCLUSION FMN can ameliorate retinal NV via the HIF-1α/VEGF Signaling pathway, and it may become a potential drug for the prevention and treatment of diabetic retinopathy.
Cristina Espinosadiez - One of the best experts on this subject based on the ideXlab platform.
-
microrna regulation of the mrn complex impacts dna damage cellular senescence and angiogenic Signaling
Cell Death and Disease, 2018Co-Authors: Cristina Espinosadiez, Raeanna Wilson, Namita Chatterjee, Clayton Hudson, Rebecca Ruhl, Christina Hipfinger, Erin Helms, Omar F. Khan, Daniel G. Anderson, Sudarshan AnandAbstract:MicroRNAs (miRs) contribute to biological robustness by buffering cellular processes from external perturbations. Here we report an unexpected link between DNA damage response and angiogenic Signaling that is buffered by a miR. We demonstrate that genotoxic stress-induced miR-494 inhibits the DNA repair machinery by targeting the MRE11a-RAD50-NBN (MRN) complex. Gain- and loss-of-function experiments show that miR-494 exacerbates DNA damage and drives endothelial senescence. Increase of miR-494 affects telomerase activity, activates p21, decreases pRb pathways, and diminishes angiogenic sprouting. Genetic and pharmacological disruption of the MRN pathway decreases VEGF Signaling, phenocopies miR-494-induced senescence, and disrupts angiogenic sprouting. Vascular-targeted delivery of miR-494 decreases both growth factor-induced and tumor angiogenesis in mouse models. Our work identifies a putative miR-facilitated mechanism by which endothelial cells can be insulated against VEGF Signaling to facilitate the onset of senescence and highlight the potential of targeting DNA repair to disrupt pathological angiogenesis.
-
microrna regulation of the mrn complex impacts dna damage cellular senescence and angiogenic Signaling
bioRxiv, 2018Co-Authors: Cristina Espinosadiez, Raeanna Wilson, Namita Chatterjee, Clayton Hudson, Rebecca Ruhl, Christina Hipfinger, Erin Helms, Omar F. Khan, Daniel G. Anderson, Sudarshan AnandAbstract:MicroRNAs contribute to biological robustness by buffering cellular processes from external perturbations. Here we report an unexpected link between DNA damage response and angiogenic Signaling that is buffered by two distinct microRNAs. We demonstrate that genotoxic stress-induced miR-494 and miR-99b inhibit the DNA repair machinery by targeting the MRE11a-RAD50-NBN (MRN) complex. Functionally, gain and loss of function experiments show that miR-494 and miR-99b affect telomerase activity, activate p21 and Rb pathways and diminish angiogenic sprouting in vitro and in vivo. Genetic and pharmacological disruption of VEGFR-2 Signaling and the MRN complex reveal a surprising co-dependency of these pathways in regulating endothelial senescence and proliferation. Vascular-targeted delivery of miR-494 decreases both growth factor -induced and tumor angiogenesis in mouse models. Mechanistically, disruption of the MRN complex induced CD44, a known driver of senescence and regulator of VEGF Signaling in addition to suppressing IL-13 a stimulator of VEGF Signaling. Our work identifies a putative miR-facilitated mechanism by which endothelial cells can be insulated against VEGF Signaling to facilitate the onset of senescence and highlight the potential of targeting DNA repair to disrupt pathological angiogenesis.
