Angiogeneses
Abstract
Tumor vascular normalization prevents tumor cells from breaking through the basement membrane and entering the vasculature, and then inhibiting metastasis initiation. In this study, we reported that the anti-tumor peptide JP1 regulates the mitochondria metabolic reprogramming through AMPK/FOXO3a/UQCRC2 signaling, which improves the tumor microenvironment hypoxia. The oxygen-rich tumor microenvironment inhibits the secretion of interleukin-8 (IL8) by tumor cells, thereby promoting tumor vascular normalization. The normalized vasculature results in mature and regular blood vessels, which makes the tumor microenvironment form benign feedback of vascular normalization, sufficient perfusion, and oxygen-rich microenvironment, prevents tumor cells from entering the vasculature and inhibits metastasis initiation. Moreover, the combined therapy of JP1 and paclitaxel (PTX) maintain a certain vascular density in the tumor, as well as promoting tumor vascular normalization, increasing the delivery of oxygen and drugs, and enhancing the anti-tumor effect. Collectively, our work highlighted a novel anti-tumor peptide JP1 to inhibit metastasis initiation and its mechanism of action.
Authors
Jiahua Cui, Zhen Che, Lu Zou, Dongyin Chen, Zhan Xie, Kun Ding, Huning Jiang, Aiping Li, Jianwei Zhou, Yongqian Shu
Abstract
Patients with peripheral artery disease (PAD) and diabetes constitute a high risk population for development of critical limb ischemia (CLI) and amputation, although the underlying mechanisms remain poorly understood. Comparison of dysregulated microRNAs from diabetic human subjects with PAD and diabetic mice with limb ischemia revealed the conserved microRNA, miR-130b-3p. In vitro angiogenic assays demonstrated miR-130b rapidly promoted proliferation, migration, and sprouting in endothelial cells (ECs), whereas miR-130b inhibition exerted anti-angiogenic effects. Local delivery of miR-130b mimics into ischemic muscles of diabetic mice (db/db) following femoral artery ligation (FAL) promoted revascularization by increasing angiogenesis and markedly improved limb necrosis and amputation. RNA-sequencing, and gene set enrichment analysis from miR-130b overexpressing ECs revealed the BMP / TGF-b signaling pathway as one of the top dysregulated pathways. Accordingly, overlapping downregulated transcripts from RNA-seq and miRNA prediction algorithms identified that miR-130b directly targeted and repressed the TGF-b superfamily member inhibin-b-A (INHBA). miR-130b overexpression or siRNA-mediated knockdown of INHBA induced IL-8 expression, a potent angiogenic chemokine. Lastly, ectopic delivery of silencer RNAs (siRNA) targeting Inhba in db/db ischemic muscles following FAL improved revascularization and limb necrosis, recapitulating the phenotype of miR-130b delivery. Taken together, a miR-130b-INHBA signaling axis may provide therapeutic targets for patients with PAD and diabetes at risk of developing CLI.
Authors
Henry S. Cheng, Daniel Pérez-Cremades, Rulin Zhuang, Anurag Jamaiyar, Winona W. Wu, Jingshu Chen, Aspasia Tzani, Lauren Stone, Jorge Plutzky, Terence E. Ryan, Philip P. Goodney, Mark A. Creager, Marc S. Sabatine, Marc P. Bonaca, Mark W. Feinberg
Abstract
Glioblastoma is amongst the deadliest human cancers and is highly vascularized. Angiogenesis is very dynamic during brain development, almost quiescent in the adult brain but reactivated in vascular-dependent CNS pathologies including brain tumors. The onco-fetal axis describes the reactivation of fetal programs in tumors, but its relevance in endothelial- and perivascular cells of the human brain vasculature in glial brain tumors is unexplored. Nucleolin is a regulator of cell proliferation and angiogenesis, but its roles in the brain vasculature remain unknown. Here, we studied the expression of Nucleolin in the neurovascular unit in human fetal brains, adult brains and human gliomas in vivo and its effects on sprouting angiogenesis and endothelial metabolism in vitro. Nucleolin is highly expressed in endothelial- and perivascular cells during brain development, downregulated in the adult brain, and upregulated in glioma. Moreover, Nucleolin expression correlated with glioma malignancy in vivo. In culture, siRNA-mediated Nucleolin knock-down reduced human brain endothelial cell (HCMEC) and human umbilical vein endothelial cell (HUVEC) sprouting angiogenesis, proliferation, filopodia extension, and glucose metabolism. Furthermore, inhibition of Nucleolin with the aptamer AS1411 decreased brain endothelial cell proliferation in vitro. Mechanistically, Nucleolin knock-down in HCMECs and HUVECs uncovered regulation of angiogenesis involving VEGFR2 and of endothelial glycolysis. These findings identify Nucleolin as a neurodevelopmental factor reactivated in glioma that promotes sprouting angiogenesis and endothelial metabolism, characterizing Nucleolin as an onco-fetal protein. Our findings have potential implications in the therapeutic targeting of glioma.
Authors
Marc Schwab, Ignazio de Trizio, Moheb Ghobrial, Jau-Ye Shiu, Oguzkan Sürücü, Francesco Girolamo, Mariella Errede, Murat Yilmaz, Johannes Haybaeck, Alessandro Moiraghi, Philippe P. Monnier, Sean E. Lawler, Jeffrey P. Greenfield, Ivan Radovanovic, Karl Frei, Ralph Schlapbach, Viola Vogel, Daniela Virgintino, Katrien De Bock, Thomas Wälchli
A miRNA-CXCR4 signaling axis impairs monopoiesis and angiogenesis in diabetic critical limb ischemia
Abstract
Patients with peripheral artery disease (PAD) and diabetes have the highest risk of critical limb ischemia (CLI) and amputation, yet the underlying mechanisms remain incompletely understood. MicroRNA (miRNA)-sequencing of plasma from diabetic patients with or without CLI was compared to diabetic mice with acute or subacute limb ischemia to identify conserved miRNAs. miRNA knockout mice on high fat diet were generated to explore impact on CLI. Comparison of dysregulated miRNAs from diabetic human subjects with PAD and diabetic mice with limb ischemia revealed conserved miR-181 family members. High fat-fed, diabetic Mir181a2b2 knockout (KO) mice had impaired revascularization in limbs due to abrogation of circulating Ly6Chi monocytes with reduced accumulation in ischemic skeletal muscles. M2-like KO macrophages under diabetic conditions failed to produce pro-angiogenic cytokines. Single cell transcriptomics of the bone marrow niche revealed that the reduced monocytosis in diabetic KO mice is a result of impaired hematopoiesis with increased CXCR4 signaling in bone marrow Lineage-Sca1+Kit+ (LSK) cells. Exogenous Ly6Chi monocytes from non-diabetic KO mice rescued the impaired revascularization in ischemic limbs of diabetic KO mice. Increased Cxcr4 expression is mediated by the novel miR-181 target, Plac8. Taken together, MiR-181a/b is a putative mediator of diabetic CLI and contributes to alterations in hematopoiesis, monocytosis, and macrophage polarization.
Authors
Henry S. Cheng, Rulin Zhuang, Daniel Pérez-Cremades, Jingshu Chen, Anurag Jamaiyar, Winona Wu, Grasiele Sausen, Aspasia Tzani, Jorge Plutzky, Jorge Henao-Mejia, Philip P. Goodney, Mark A. Creager, Marc S. Sabatine, Marc P. Bonaca, Mark W. Feinberg
Abstract
Loss of function mutations in CCM genes and gain of function mutation in the MAP3K3 gene encoding MEKK3 cause cerebral cavernous malformation (CCM). Deficiency of CCM proteins leads to the activation of MEKK3-KLF2/4 signaling, but it is not clear how this occurs. Here we demonstrate that deletion of the CCM3 interacting kinases STK24/25 in endothelial cells cause defects in vascular patterning during development as well as CCM lesion formation during postnatal life. While permanent deletion of STK24/25 in endothelial cells caused developmental defects of the vascular system, inducible postnatal deletion of STK24/25 impaired angiogenesis in the retina and brain. More importantly, deletion of STK24/25 in neonatal mice led to the development of severe CCM lesions. At the molecular level, a hybrid protein consisting of the STK kinase domain and the MEKK3 interacting domain of CCM2 rescued the vascular phenotype caused by the loss of ccm gene function in zebrafish. Our study suggests that CCM2/3 proteins act as adapters to allow recruitment of STK24/25 to limit the constitutive MEKK3 activity that contributes to vessel stability. Loss of STK24/25 causes MEKK3 activation leading to CCM lesion formation.
Authors
Xi Yang, Shi-Ting Wu, Rui Gao, Rui Wang, Yixuan Wang, Zhenkun Dong, Lu Wang, Chunxiao Qi, Xiaohong Wang, M. Lienhard Schmitz, Renjing Liu, Zhiming Han, Lu Wang, Xiangjian Zheng
Abstract
Pathological angiogenesis is a major cause of irreversible blindness in individuals of all age groups with proliferative retinopathy (PR). Mononuclear phagocytes (MPs) within neovascular areas contribute to aberrant retinal angiogenesis. Due to their cellular heterogeneity, defining the roles of MP subsets in PR onset and progression has been challenging. Here, we aimed to investigate the heterogeneity of microglia associated with neovascularization and characterize the transcriptional profiles and metabolic pathways of pro-angiogenic microglia in a mouse model of oxygen-induced proliferative retinopathy (OIR). Using transcriptional single-cell sorting, we comprehensively map all microglia populations in retinas of room air (RA) and OIR mice. We unveil several unique types of PR-associated microglia (PRAM) and identify markers, signaling pathways, and regulons associated with these cells. Among these microglia subpopulations, we found a highly proliferative microglia subset with high self-renewal capacity and a hyper-metabolic microglia subset that expresses high levels of activating microglia markers, glycolytic enzymes and pro-angiogenic insulin-like growth factor 1. Immunohistochemical staining shows these PRAMs were spatially located within or around neovascular (NV) tufts. These unique microglia-types have the potential to promote retinal angiogenesis, which may have important implications for future treatment of PR and other pathological ocular angiogenesis-related diseases.
Authors
Zhiping Liu, Huidong Shi, Jiean Xu, Qiuhua Yang, Qian Ma, Xiaoxiao Mao, Zhimin Xu, Yaqi Zhou, Qingen Da, Yongfeng Cai, David J.R. Fulton, Zheng Dong, Akrit Sodhi, Ruth B. Caldwell, Yuqing Huo
Abstract
The (Pro)renin receptor ((P)RR), also known as ATP6AP2, is a single-transmembrane protein that is implicated in a multitude of biological processes. However, the exact role of ATP6AP2 during blood vessel development remains largely undefined. Here, we use an inducible endothelial cell (EC)-specific Atp6ap2 knockout mouse model to investigate the role of ATP6AP2 during both physiological and pathological angiogenesis in vivo. We observed that postnatal deletion of Atp6ap2 in ECs results in cell migration defects, loss of tip cell polarity and subsequent impairment of retinal angiogenesis. In vitro, Atp6ap2 deficient ECs similarly displayed reduced cell migration, impaired sprouting, and defective cell polarity. Transcriptional profiling of ECs isolated from Atp6ap2 mutant mice further indicated regulatory roles in angiogenesis, cell migration and extracellular matrix composition. Mechanistically, we provided evidence that expression of various extracellular matrix components is controlled by ATP6AP2 via the extracellular-signal-regulated kinase (ERK) pathway. Furthermore, Atp6ap2 deficient retinas exhibited reduced revascularization in an oxygen induced retinopathy model. Collectively, our results demonstrated a critical role of ATP6AP2 as a regulator of developmental and pathological angiogenesis.
Authors
Nehal R. Patel, Rajan K C, Avery E. Blanks, Yisu Li, Minolfa C. Prieto, Stryder M. Meadows
Abstract
Blood clot formation initiates ischemic events, but coagulation roles during postischemic tissue repair are poorly understood. The endothelial protein C receptor (EPCR) regulates coagulation as well as immune and vascular signaling by protease activated receptors (PARs). Here, we show that endothelial EPCRPAR1 signaling supports reperfusion and neovascularization in hindlimb ischemia in mice. Whereas deletion of PAR2 or PAR4 did not impair angiogenesis, EPCR and PAR1 deficiency or PAR1 resistance to cleavage by activated protein C caused markedly reduced postischemic reperfusion in vivo and angiogenesis in vitro. These findings were corroborated by biased PAR1 agonism in isolated primary endothelial cells. Loss of EPCRPAR1 signaling upregulated hemoglobin expression and reduced endothelial nitric oxide (NO) bioavailability. Defective angiogenic sprouting was rescued by the NO donor DETA-NO, whereas NO scavenging increased hemoglobin and mesenchymal marker expression in human and mouse endothelial cells. Vascular specimens from patients with ischemic peripheral artery disease exhibited increased hemoglobin expression, and soluble EPCR and NO levels were reduced in plasma. Our data implicate endothelial EPCR−PAR1 signaling in the hypoxic response of endothelial cells and identify suppression of hemoglobin expression as an unexpected link between coagulation signaling, preservation of endothelial cell NO bioavailability, support of neovascularization, and prevention of fibrosis.
Authors
Magdalena L. Bochenek, Rajinikanth Gogiraju, Stefanie Großmann, Janina Krug, Jennifer Orth, Sabine Reyda, George S. Georgiadis, Henri Spronk, Stavros Konstantinides, Thomas Münzel, John H. Griffin, Philipp S. Wild, Christine Espinola-Klein, Wolfram Ruf, Katrin Schäfer
Abstract
Arginine methylation mediated by protein arginine methyltransferases (PRMTs) has been shown to be an important posttranslational mechanism involved in various biological processes. Herein, we sought to investigate whether PRMT5, a major type II enzyme, is involved in pathological angiogenesis and, if so, to elucidate the molecular mechanism involved. Our results show that PRMT5 expression is significantly upregulated in ischemic tissues and hypoxic endothelial cells (ECs). Endothelial-specific Prmt5-KO mice were generated to define the role of PRMT5 in hindlimb ischemia–induced angiogenesis. We found that these mice exhibited impaired recovery of blood perfusion and motor function of the lower limbs, an impairment that was accompanied by decreased vascular density and increased necrosis as compared with their WT littermates. Furthermore, both pharmacological and genetic inhibition of PRMT5 significantly attenuated EC proliferation, migration, tube formation, and aortic ring sprouting. Mechanistically, we showed that inhibition of PRMT5 markedly attenuated hypoxia-induced factor 1-α (HIF-1α) protein stability and vascular endothelial growth factor–induced (VEGF-induced) signaling pathways in ECs. Our results provide compelling evidence demonstrating a crucial role of PRMT5 in hypoxia-induced angiogenesis and suggest that inhibition of PRMT5 may provide novel therapeutic strategies for the treatment of abnormal angiogenesis-related diseases, such as cancer and diabetic retinopathy.
Authors
Qing Ye, Jian Zhang, Chen Zhang, Bing Yi, Kyosuke Kazama, Wennan Liu, Xiaobo Sun, Yan Liu, Jianxin Sun
Abstract
Malignant pleural effusion (MPE) is an incurable common manifestation of many malignancies. Its formation is orchestrated by complex interactions among tumor cells, inflammatory cells, and the vasculature. Tumor-associated macrophages present the dominant inflammatory population of MPE, and M2 macrophage numbers account for dismal prognosis. M2 polarization is known to be triggered by CSF1/CSF1 receptor (CSF1R) signaling. We hypothesized that CSF1R+ M2 macrophages favor MPE formation and could be therapeutically targeted to limit MPE. We generated mice with CSF1R-deficient macrophages and induced lung and colon adenocarcinoma–associated MPE. We also examined the therapeutic potential of a clinically relevant CSF1R inhibitor (BLZ945) in lung and colon adenocarcinoma–induced experimental MPE. We showed that CSF1R+ macrophages promoted pleural fluid accumulation by enhancing vascular permeability, destabilizing tumor vessels, and favoring immune suppression. We also showed that CSF1R inhibition limited MPE in vivo by reducing vascular permeability and neoangiogenesis and impeding tumor progression. This was because apart from macrophages, CSF1R signals in cancer-associated fibroblasts leading to macrophage inflammatory protein 2 secretion triggered the manifestation of suppressive and angiogenic properties in macrophages upon CXCR2 paracrine activation. Pharmacological targeting of the CSF1/CSF1R axis can therefore be a vital strategy for limiting MPE.
Authors
Chrysavgi N. Kosti, Photene C. Vaitsi, Apostolos G. Pappas, Marianthi P. Iliopoulou, Katherina K. Psarra, Sophia F. Magkouta, Ioannis T. Kalomenidis
No posts were found with this tag.
