Angiogenesis最新文献

Angiogenesis is a crucial component of various physiological and pathological processes, including embryonic development, ischemic diseases, and tumor progression. Recent studies have highlighted the importance of ubiquitinases in angiogenesis. In this study, we utilized RNA sequencing data of the mouse retinal development model from the GEO database to identify the potential proangiogenic deubiquitinases and found USP11 was significantly upregulated. Although USP11 is known to regulate cell survival, DNA repair, and oxidative stress in cancers and ischemic conditions, its direct role in endothelial angiogenesis remains poorly understood. Here, we demonstrated that USP11 expression correlates with key pro-angiogenic genes and is significantly upregulated at both mRNA and protein levels in VEGF-treated human umbilical vein endothelial cells (HUVECs). USP11 knockout markedly inhibited angiogenesis both in vivo and in vitro, whereas USP11 overexpression promoted angiogenesis. Mechanistically, USP11 binds to PRDX2, facilitating the removal of its K63-linked polyubiquitination, which promotes its translocation into the nucleus. This facilitates the concurrent nuclear translocation of c-MYC, a PRDX2 interactor, which subsequently enhances the transcription of KDR (encoding VEGFR2) and activates the VEGFR2 signaling pathway. Our findings suggest that USP11 promotes angiogenesis by upregulating VEGFR2 expression through the PRDX2/c-MYC pathway, indicating that USP11 could serve as a potential target for clinical interventions in angiogenesis-related diseases.

The vascular endothelial growth factor VEGF drives excessive vascular permeability to cause tissue-damaging oedema in neovascular and inflammatory diseases across multiple organs. Several molecular pathways have been implicated in VEGF-induced hyperpermeability, including binding of the VEGF-activated tyrosine kinase receptor VEGFR2 by the T-cell specific adaptor (TSAd) to recruit a SRC family kinase to induce junction opening between vascular endothelial cells (ECs). Inconsistent with a universal role for TSAd in permeability signalling, immunostaining approaches previously reported TSAd only in dermal and kidney vasculature. To address this discrepancy, we have mined publicly available omics data for expression of TSAd and other permeability-relevant signal transducers in multiple organs affected by VEGF-induced vascular permeability. Unexpectedly, TSAd transcripts were largely absent from EC single cell RNAseq data, whereas transcripts for other permeability-relevant signal transducers were detected readily. TSAd transcripts were also lacking from half of the EC bulk RNAseq datasets examined, and in the remaining datasets appeared at low levels concordant with models of leaky transcription. Epigenomic EC data located the TSAd promoter to closed chromatin in ECs, and mass spectrometry-derived EC proteomes typically lacked TSAd. By suggesting that TSAd is not actively expressed in ECs, our findings imply that TSAd is likely not critical for linking VEGFR2 to downstream signal transducers for EC junction opening.

Cord blood-derived endothelial colony-forming cells (CB-ECFCs) hold significant promise for regenerative medicine due to their unique vasculogenic and immunomodulatory properties. These cells exhibit a superior proliferative capacity, robust ability to form vascular networks, and lower immunogenicity compared to adult and embryonic stem cell-derived counterparts. The immune-privileged characteristics of CB-ECFCs, including reduced expression of pro-inflammatory mediators and tolerance-inducing molecules such as HLA-G, further enhance their therapeutic potential. Their low immunogenicity minimizes the risk of immune rejection, making them suitable for allogenic cell therapies. Their application extends to complex tissue engineering and organ revascularization, where their ability to integrate into three-dimensional scaffolds and support vascular tree formation represents a significant advancement. Moreover, CB-ECFCs’ capability to adapt to inflammatory stimuli and retain immunological memory highlights their functional versatility in dynamic microenvironments. This review highlights the remarkable ontogeny of ECFCs while unveiling the unparalleled potential of CB-ECFCs in revolutionizing regenerative medicine. From pre-vascularizing engineered tissues and organoids to pioneering cell-based therapies for cardiovascular, dermatological, and degenerative diseases, CB-ECFCs stand at the forefront of cutting-edge biomedical advancements, offering unprecedented opportunities for therapeutic innovation. By leveraging their vasculogenic, immune-regulatory, and regenerative capacities, CB-ECFCs offer a robust alternative for addressing the challenges of vascular repair and organ engineering. Future research should focus on unraveling their transcriptomic and functional profiles to optimize clinical applications and advance the field of regenerative medicine.

With interest growing in modeling more complex aspects of human disease in the laboratory, the need for effectively vascularizing human tissue models is becoming paramount. However, fully recreating human tissue microvasculatures is challenging given the multicellular complexity of the microvessel and microvessel-tissue interplay. Importantly, effective models should capture the dynamic activity of the perivascular cells of the perivascular niche, which are critical to tissue hemostasis and function. Isolated microvessel fragments from rodent adipose have been extensively studied and used in a variety of vascularization models. We have progressed this proven technology by deriving isolated fragments of intact human microvessels harvested from adipose (haMVs) to model human vascularization and advance human vascularized tissue models. Here we show the haMVs retain native microvessel structures, including perivascular cellularity, and recapitulate bona fide sprouting angiogenesis in vitro through distinct sprouting and neovessel elongation phases. As primary isolates, the angiogenic potential varies between donor lots and correlates with the presence of haMV perivascular cells. In an in vitro model of tumor angiogenesis, the addition of anti-tumor agents impacted tumor cell expansion in the presence of the haMVs but not endothelial cells alone demonstrating the importance of the perivascular cells in tissue modeling. The human adipose microvessels offer, in a single reagent, a more complex, dynamic human tissue model vascularization solution.

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Microvascular aging, predominantly driven by endothelial cells (ECs) dysfunction, is a critical early event in cardiovascular diseases. However, the specific effects of aging on ECs across the microvascular network segments and the associated mechanisms are not fully understood. In this study, we detected a microvascular rarefaction and a decreased proportion of venular ECs in the subcutaneous adipose tissue of aged mice using light-sheet immunofluorescence microscopy and single-cell RNA sequencing. Moreover, aged ECs, especially in the venular subtype, exhibited a pseudotemporal transition to a terminal state characterized by diminished oxidative phosphorylation and strengthened cytokine signaling. Metabolic flux balance analysis predicted that among the 13 differentially expressed cytokines identified in aged EC subpopulations, Cxcl9 was strongly correlated with impaired oxidative phosphorylation in aged ECs. It was further validated using microvascular ECs treated with Cxcl9. Notably, the G protein-coupled receptor signaling pathway was subsequently suppressed, in which Aplnr suppression was also observed in aged ECs, contributing to their impaired energy metabolism and reduced angiogenesis. Based on these findings, we propose Cxcl9 as a biomarker for aging-related dysfunction of microvascular ECs, suggesting that targeting Cxcl9 signaling may help combat microvascular aging.

Liver sinusoidal endothelial cells (LSECs), with their unique morphology and function, have garnered increasing attention in chronic liver disease research. This review summarizes the critical roles of LSECs under physiological conditions and in two representative chronic liver diseases: metabolic dysfunction-associated steatotic liver disease (MASLD) and liver cancer. Under physiological conditions, LSECs act as selective barriers, regulating substance exchange and hepatic blood flow. Interestingly, LSECs exhibit contrasting roles at different stages of disease progression: in the early stages, they actively resist disease advancement and help restore sinusoidal homeostasis; whereas in later stages, they contribute to disease worsening. During this transition, LSECs undergo capillarization, lose their characteristic markers, and become dysfunctional. As the disease progresses, LSECs closely interact with hepatocytes, hepatic stellate cells, various immune cells, and tumor cells, driving processes such as steatosis, inflammation, fibrosis, angiogenesis, and carcinogenesis. Consequently, targeting LSECs represents a promising therapeutic strategy for chronic liver diseases. Relevant therapeutic targets and potential drugs are summarized in this review.

Inhibition of angiogenesis, either as monotherapy or in conjunction with other treatments, holds significant promise in cancer treatment. However, the limited efficacy of clinically approved anti-angiogenic agents underscores the urgent need for the development of novel drugs and therapeutic strategies. In this study, we demonstrate the highly selective inhibitory effects of clioquinol, a topical antifungal and antibiotic agent, on the angiogenic activity of endothelial cells (ECs) in a series of in vitro angiogenesis assays. Moreover, clioquinol effectively suppressed blood vessel formation in ex vivo aortic ring and in vivo Matrigel plug assays. Mechanistic studies revealed that clioquinol directly binds to the ATP-binding site of vascular endothelial growth factor receptor 2 (VEGFR2), promoting its degradation through both proteasome and lysosome pathways. This led to the down-regulation of the downstream extracellular signal-regulated kinase (ERK) pathway. In addition, the combination with the AKT inhibitor MK-2206 synergistically boosted the anti-angiogenic efficacy of clioquinol in vitro and in an in vivo dorsal skinfold chamber model of triple-negative breast cancer (TNBC), leading to the suppression of TNBC growth. Accordingly, clioquinol, either alone or in combination with AKT inhibitors, represents a promising therapeutic agent for future anti-angiogenic cancer treatment.