Angiogenesis
Abstract
Infantile hemangioma is a vascular tumor characterized by the rapid growth of disorganized blood vessels followed by slow spontaneous involution. The underlying molecular mechanisms that regulate hemangioma proliferation and involution still are not well elucidated. Our previous studies reported that NOGOB receptor (NGBR), a transmembrane protein, is required for the translocation of prenylated RAS from the cytosol to the plasma membrane and promotes RAS activation. Here, we show that NGBR is highly expressed in the proliferating phase of infantile hemangioma, but its expression decreases in the involuting phase, suggesting that NGBR may be involved in regulating the growth of proliferating hemangioma. Moreover, we demonstrated that NGBR knockdown in hemangioma stem cells (HemSCs) attenuates growth factors-stimulated RAS activation and diminishes the migration and proliferation of HemSCs, which is consistent with the effects of RAS knockdown in HemSCs. In vivo differentiation assay further showed that NGBR knockdown inhibits blood vessel formation and adipocyte differentiation of HemSCs in immunodeficient mice. Our data suggest that NGBR serves as a RAS modulator in controlling the growth and differentiation of HemSCs.
Authors
Wenquan Hu, Zhong Liu, Valerie Salato, Paula E. North, Joyce Bischoff, Suresh N. Kumar, Zhi Fang, Sujith Rajan, M. Mahmood Hussain, Qing R. Miao
Abstract
Successful implantation is associated with a unique spatial pattern of vascular remodeling, characterized by profound peripheral neovascularization surrounding a periembryo avascular niche. We hypothesized that hyaluronan controls the formation of this distinctive vascular pattern encompassing the embryo. This hypothesis was evaluated by genetic modification of hyaluronan metabolism, specifically targeted to embryonic trophoblast cells. The outcome of altered hyaluronan deposition on uterine vascular remodeling and postimplantation development were analyzed by MRI, detailed histological examinations, and RNA sequencing of uterine NK cells. Our experiments revealed that disruption of hyaluronan synthesis, as well as its increased cleavage at the embryonic niche, impaired implantation by induction of decidual vascular permeability, defective vascular sinus folds formation, breach of the maternal-embryo barrier, elevated MMP-9 expression, and interrupted uterine NK cell recruitment and function. Conversely, enhanced deposition of hyaluronan resulted in the expansion of the maternal-embryo barrier and increased diffusion distance, leading to compromised implantation. The deposition of hyaluronan at the embryonic niche is regulated by progesterone-progesterone receptor signaling. These results demonstrate a pivotal role for hyaluronan in successful pregnancy by fine-tuning the periembryo avascular niche and maternal vascular morphogenesis.
Authors
Ron Hadas, Eran Gershon, Aviad Cohen, Ofir Atrakchi, Shlomi Lazar, Ofra Golani, Bareket Dassa, Michal Elbaz, Gadi Cohen, Raya Eilam, Nava Dekel, Michal Neeman
Abstract
Arteriovenous malformations (AVMs) are high-flow lesions directly connecting arteries and veins. In the brain, AVM rupture can cause seizures, stroke, and death. Patients with AVMs exhibit reduced coverage of the vessels by pericytes, the mural cells of microvascular capillaries; however, the mechanism underlying this pericyte reduction and its association with AVM pathogenesis remains unknown. Notch signaling has been proposed to regulate critical pericyte functions. We hypothesized that Notch signaling in pericytes is crucial to maintain pericyte homeostasis and prevent AVM formation. We inhibited Notch signaling specifically in perivascular cells and analyzed the vasculature of these mice. The retinal vessels of mice with deficient perivascular Notch signaling developed severe AVMs, together with a significant reduction in pericytes and vascular smooth muscle cells (vSMC) in the arteries, while vSMCs were increased in the veins. Vascular malformations and pericyte loss were also observed in the forebrain of embryonic mice deficient for perivascular Notch signaling. Moreover, the loss of Notch signaling in pericytes downregulated Pdgfrb levels and increased pericyte apoptosis, pointing to a critical role for Notch in pericyte survival. Overall, our findings reveal a mechanism of AVM formation and highlight the Notch signaling pathway as an essential mediator in this process.
Authors
Taliha Nadeem, Wil Bogue, Bianca Bigit, Henar Cuervo
Abstract
Angiogenesis is essential for cardiac functional recovery after myocardial infarction (MI). HSPA12B is predominately expressed in endothelial cells and required for angiogenesis. Yes-associated protein (YAP) plays an important role in tumor angiogenesis. This study investigated the cooperative role of HSPA12B and YAP in angiogenesis post-MI. Silencing of either HSPA12B or YAP impairs hypoxia-promoted endothelial cell proliferation and angiogenesis. Deficiency of HSPA12B suppresses YAP expression and nuclear translocation following hypoxia. Knockdown of YAP attenuates hypoxia-stimulated HSPA12B nuclear translocation and abrogates HSPA12B-promoted endothelial cell angiogenesis. Mechanistically, hypoxia induced an interaction between endothelial HSPA12B and YAP. ChIP assay shows that HSPA12B is a target gene of YAP/transcriptional enhanced associated domain4 (TEAD4) and a co-activator in YAP-associated angiogenesis. In vivo studies using the MI model show that endothelial specific deficiency of HSPA12B (eHspa12b-/-) or YAP (eYap-/-) impairs angiogenesis and exacerbates cardiac dysfunction, when compared with wild type (WT) mice. MI increased YAP expression and nuclear translocation in WT hearts, but not in eHspa12b-/- hearts. HSPA12B expression and nuclear translocation were up-regulated in WT MI hearts, but not in eYap-/- MI myocardium. Our data demonstrated that endothelial HSPA12B is a novel target and co-activator for YAP/TEAD4 and cooperates with YAP to regulate endothelial angiogenesis post-MI.
Authors
Min Fan, Kun Yang, Xiaohui Wang, Yana Wang, Fei Tu, Tuanzhu Ha, Li Liu, David L. Williams, Chuanfu Li
Abstract
Oxidative stress and inadequate redox homeostasis is crucial for tumor initiation and progression. MTH1 (NUDT1) enzyme prevents incorporation of oxidized dNTPs by sanitizing the deoxynucleoside triphosphate (dNTP) pool and is therefore vital for the survival of tumor cells. MTH1 inhibition has been found to inhibit the growth of several experimental tumors, but its role in mesothelioma progression remained elusive. Moreover, although MTH1 is nonessential to normal cells, its role in survival of host cells in tumor milieu, especially tumor endothelium, is unclear. We validated a clinically relevant MTH1 inhibitor (Karonudib) in mesothelioma treatment using human xenografts and syngeneic murine models. We show that MTH1 inhibition impedes mesothelioma progression and that inherent tumoral MTH1 levels are associated with a tumor’s response. We also identified tumor endothelial cells as selective targets of Karonudib and propose a model of intercellular signaling among tumor cells and bystander tumor endothelium. We finally determined the major biological processes associated with elevated MTH1 gene expression in human mesotheliomas.
Authors
Sophia F. Magkouta, Apostolos G. Pappas, Photene C. Vaitsi, Panagiotis C. Agioutantis, Ioannis S. Pateras, Charalampos A. Moschos, Marianthi P. Iliopoulou, Chrysavgi N. Kosti, Heleni V. Loutrari, Vassilis G. Gorgoulis, Ioannis T. Kalomenidis
Abstract
Following myocardial infarction (MI), the adult heart has minimal regenerative potential. Conversely, the neonatal heart can undergo extensive regeneration, and neovascularisation capacity was hypothesised to contribute to this difference. Here, we demonstrate the higher angiogenic potential of neonatal compared to adult mouse cardiac endothelial cells (MCECs) in vitro and use this difference to identify candidate microRNAs (miRs) regulating cardiac angiogenesis after MI. MiR expression profiling revealed miR-96 and miR-183 upregulation in adult compared to neonatal MCECs. Their overexpression decreased the angiogenic potential of neonatal MCECs in vitro and prevented scar resolution and neovascularisation in neonatal mice after MI. Inversely, their inhibition improved the angiogenic potential of adult MCECs, and miR-96/miR-183 knock-out mice had increased peri-infarct neovascularisation. In silico analyses identified anillin (ANLN) as a direct target of miR-96 and miR-183. In agreement, Anln expression declined following their overexpression and increased after their inhibition in vitro. Moreover, ANLN expression inversely correlated with miR-96 expression and age in cardiac ECs of cardiovascular patients. In vivo, ANLN-positive vessels were enriched in the peri-infarct area of miR-96/miR-183 knock-out mice. These findings identify miR-96 and miR-183 as regulators of neovascularisation following MI and miR-regulated genes such as anillin as potential therapeutic targets for cardiovascular disease.
Authors
Raphael F.P. Castellan, Milena Vitiello, Martina Vidmar, Steven Johnstone, Dominga Iacobazzi, David Mellis, Benjamin Cathcart, Adrian JW Thomson, Christiana Ruhrberg, Massimo Caputo, David E. Newby, Gillian A. Gray, Andrew Howard Baker, Andrea Caporali, Marco Meloni
Abstract
Abnormal subretinal neovascularization is characteristic of vision-threatening retinal diseases including macular telangiectasia (MacTel) and retinal angiomatous proliferation (RAP). Subretinal neovascular tufts and photoreceptor dysfunction are observed in very low-density lipoprotein receptor mutant mice (Vldlr–/–). These changes mirror those observed in MacTel and RAP patients, but the pathogenesis is largely unknown. In this study, we show that retinal microglia are closely associated with retinal neovascular tufts in Vldlr–/– mice and retinal tissue from MacTel patients; ablation of microglia/macrophages dramatically prevents formation of retinal neovascular tufts and improves neuronal function as assessed by electroretinography. VMD2-driven retinal pigmented epithelium (RPE)-specific knockouts of VEGF greatly reduced subretinal infiltration of microglia/macrophages, subsequently reducing NV tufts. These findings highlight the contribution of microglia/macrophages to the pathogenesis of NV, provide valuable clues regarding potential causative cellular mechanisms for subretinal neovascularization in MacTel and RAP patients, and suggest that targeting microglia activation may be a therapeutic option in these diseases.
Authors
Ayumi Usui-Ouchi, Yoshihiko Usui, Toshihide Kurihara, Edith Aguilar, Michael I. Dorrell, Yoichiro Ideguchi, Susumu Sakimoto, Stephen Bravo, Martin Friedlander
Abstract
Increased subchondral bone angiogenesis with blood vessels breaching the tidemark into the avascular cartilage is a diagnostic feature of human osteoarthritis. However, the mechanisms that initiate subchondral bone angiogenesis remain unclear. We show that abnormally increased platelet-derived growth factor-BB (PDGF-BB) secretion by mononuclear preosteoclasts induces subchondral bone angiogenesis, contributing to osteoarthritis development. In mice after destabilization of the medial meniscus (DMM), aberrant joint subchondral bone angiogenesis developed during an early stage of osteoarthritis, before articular cartilage damage occurred. Mononuclear preosteoclasts in subchondral bone secrete excessive amounts of PDGF-BB, which activates platelet-derived growth factor receptor β (PDGFRβ) signaling in pericytes for neo-vessel formation. Selective knockout of PDGF-BB in preosteoclasts attenuates subchondral bone angiogenesis and abrogates joint degeneration and subchondral innervation induced by DMM. Transgenic mice that express PDGF-BB in preosteoclasts recapitulate pathological subchondral bone angiogenesis and develop joint degeneration and subchondral innervation spontaneously. Our study provides the first evidence that PDGF-BB derived from preosteoclasts is a key driver of pathological subchondral bone angiogenesis during osteoarthritis development and offers a new avenue for developing early treatments for this disease.
Authors
Weiping Su, Guanqiao Liu, Xiaonan Liu, Yangying Zhou, Qi Sun, Gehua Zhen, Xiao Wang, Yihe Hu, Peisong Gao, Shadpour Demehri, Xu Cao, Mei Wan
Abstract
Retinopathy of prematurity (ROP) is a disorder of the developing retina of preterm infants. ROP can lead to blindness because of abnormal angiogenesis that is the result of suspended vascular development and vaso-obliteration leading to severe retinal stress and hypoxia. We tested the hypothesis that the use of the human progenitor cell combination, bone marrow–derived CD34+ cells and vascular wall–derived endothelial colony–forming cells (ECFCs), would synergistically protect the developing retinal vasculature in a mouse model of ROP, called oxygen-induced retinopathy (OIR). CD34+ cells alone, ECFCs alone, or the combination thereof were injected intravitreally at either P5 or P12 and pups were euthanized at P17. Retinas from OIR mice injected with ECFCs or the combined treatment revealed formation of the deep vascular plexus (DVP) while still in hyperoxia, with normal-appearing connections between the superficial vascular plexus (SVP) and the DVP. In addition, the combination of cells completely prevented aberrant retinal neovascularization and was more effective anatomically and functionally at rescuing the ischemia phenotype than either cell type alone. We show that the beneficial effects of the cell combination are the result of their ability to orchestrate an acceleration of vascular development and more rapid ensheathment of pericytes on the developing vessels. Lastly, our proteomic and transcriptomic data sets reveal pathways altered by the dual cell therapy, including many involved in neuroretinal maintenance, and principal component analysis (PCA) showed that cell therapy restored OIR retinas to a state that was closely associated with age-matched normal retinas. Together, these data herein support the use of dual cell therapy as a promising preventive treatment for the development of ROP in premature infants.
Authors
Sergio Li Calzi, Lynn C. Shaw, Leni Moldovan, William C. Shelley, Xiaoping Qi, Lyne Racette, Judith L. Quigley, Seth D. Fortmann, Michael E. Boulton, Mervin C. Yoder, Maria B. Grant
Abstract
Angiogenesis is a key process that allows nutrient uptake and cellular trafficking and is co-opted in cancer to enable tumor growth and metastasis. Recently, extracellular vesicles (EVs) have been shown to promote angiogenesis; however, it is unclear what unique features EVs contribute to the process. Here, we studied the role of EVs derived from head and neck squamous cell carcinoma (HNSCC) in driving tumor angiogenesis. Small EVs (SEVs), in the size range of exosomes (50-150 nm), induced angiogenesis both in vitro and in vivo. Proteomic analysis of HNSCC SEVs revealed the cell-cell signaling receptor EPHB2 as a promising candidate cargo to promote angiogenesis. Analysis of TCGA RNA-Seq and patient tissue microarray data further identified EPHB2 overexpression in HNSCC tumors to be associated with poor patient prognosis and tumor angiogenesis, especially in the context of overexpression of the exosome secretion regulator cortactin. Functional experiments revealed that EPHB2 expression in SEVs regulates angiogenesis both in vitro and in vivo and that EPHB2 carried by SEVs stimulates ephrin-B reverse signaling, inducing STAT3 phosphorylation. A STAT3 inhibitor greatly reduced SEV-induced angiogenesis. These data suggest a novel model in which EVs uniquely promote angiogenesis by transporting Eph transmembrane receptors to non-adjacent endothelial cells to induce ephrin reverse signaling.
Authors
Shinya Sato, Suhas Vasaikar, Adel Eskaros, Young Kim, James S. Lewis, Bing Zhang, Andries Zijlstra, Alissa M. Weaver
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