Angiogenesis最新文献

The renal vasculature consists of highly specialized blood vessels with distinct physiological functions. Defining their transcriptional signatures and tracing their developmental ontogeny has thus far been challenging due to a lack of regionally specific endothelial biomarkers. Here, we performed single nuclear RNA sequencing (snucRNA-Seq) to interrogate the transcriptional heterogeneity of embryonic renal endothelial cells (ECs). We identified ten endothelial subtypes, and validated regionally restricted expression of novel marker genes of glomeruli, arteries, vasa recta, and immature capillary subtypes using multiplex RNAscope. We also define previously uncharacterized and heterogeneous molecular signatures of the immature renal vasculature, including putative endothelial progenitors. We interrogate biological characteristics of immature EC types using a variety of in vivo tools. Lineage tracing of Esm1-expressing cells reveals the previously unrecognized multi-origin and multi-clonal endothelial tip cell contribution to the glomerular vasculature. Together, this study provides a validated, tool-focused developmental atlas of the murine renal vasculature and elucidates novel cellular mechanisms of nephron vascularization.

The recent study by Santos-De-La-Mata et al. (Angiogenesis 28(4): 482025, 2025) provides critical evidence that adipose-derived stem cells (ASCs) from patients with chronic spinal cord injury (SCI) and pressure injuries (PIs) exhibit significantly impaired vasculogenic potential.1 Their comparative analysis revealed deficits in key pro-angiogenic functions, including reduced proliferation, migration, tube formation, and secretion of vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) in SCI/PI-derived ASCs compared to healthy controls. These in vitro findings were corroborated by a diminished capacity to support neovascularization in an in vivo Matrigel plug assay. This cellular dysfunction underscores a fundamental mechanism contributing to refractory wound healing in this patient population and critically challenges the efficacy of autologous ASC-based therapies. This analysis discusses these findings in the context of chronic inflammatory microenvironments and epigenetic regulation,2,3 and explores potential strategies to overcome this impairment, including allogeneic cell sources4,5 and pre-conditioning techniques to rejuvenate patient-derived cells.6 The work of Santos-De-La-Mata et al. establishes a vital foundation for developing more effective, personalized regenerative medicine approaches for complex chronic wounds.

Aims

Endothelial dysfunction and impaired angiogenesis are hallmarks of ischemic heart disease and critical determinants of adverse cardiovascular outcomes after myocardial infarction (MI). While conventional cardiovascular risk factors (CVRFs) are known contributors, the specific role of MI itself triggering endothelial dysfunction remains unclear. This study aims to assess the direct impact of MI on endothelial function, independent of cardiovascular risk factors, using human and porcine endothelial colony-forming cells (ECFCs) as a surrogate cellular model.

Methods and results

Human ECFCs (hECFCs) were isolated from the peripheral blood of healthy volunteers (Control-hECFCs, n = 6), patients immediately after MI (AMI-hECFCs, n = 6), and patients 6 months after MI (CMI-hECFCs, n = 6). To evaluate the direct effect of MI independently of CVRFs, a porcine model was used: healthy pigs (n = 6) underwent 90 min of myocardial ischemia by coronary balloon occlusion followed by reperfusion. Porcine ECFCs (pECFCs) were isolated before MI (Control-pECFCs) and one month after MI (CMI-pECFCs, n = 6). In vitro, CMI-hECFCs and CMI-pECFCs had delayed colony formation, whereas AMI-hECFCs did not. Morphological alterations were observed in AMI-hECFCs and CMI-hECFCs (area and shape), while only shape changes were found in CMI-pECFCs. Senescence was increased in AMI-hECFCs and CMI-hECFCs, but not in CMI-pECFCs. Elevated oxidative stress was only detected in CMI-hECFCs. Functional angiogenic and proliferative capacities were reduced in AMI-hECFCs, CMI-hECFCs and CMI-pECFCs; however, only CMI-hECFCs and CMI-pECFCs displayed impaired migration. Molecular analysis showed overactivation of the MSK2/MKK3/p53 signalling axis in dysfunctional ECFCs, while synergistic inhibition of the axis partially restored ECFC function.

Conclusions

MI induces sustained ECFC dysfunction independently of cardiovascular risk factors. Targeting the MSK2/MKK3/p53 pathway may be a promising therapeutic strategy to restore endothelial function and improve angiogenesis after MI.

Graphical abstract

Despite advancements in diagnostic and therapeutic strategies, lung adenocarcinoma (LUAD) remains a leading cause of cancer-related mortality due to its aggressive metastatic potential. Extracellular superoxide dismutase (SOD3) is an antioxidant enzyme that regulates oxidative stress and is regarded as a tumor suppressor. However, studies have demonstrated that SOD3 can either promote or inhibit cell proliferation and survival in various cancers, and its molecular mechanisms within the tumor microenvironment are poorly understood. In this study, we report a breakthrough in uncovering the role of SOD3 derived from cancer-associated fibroblasts (CAFs) in LUAD. Using LUAD xenograft models co-implanted with SOD3-overexpressing CAFs (CAF^SOD3), we observe an aggressive tumor phenotype characterized by increased lymphangiogenesis and lymphatic vessel invasion (LVI) of the tumor. Additionally, LUAD patients with elevated SOD3 levels exhibit a higher incidence of LVI and metastasis. Notably, RNA sequencing of CAF^SOD3 reveals that SOD3-mediated VEGF-dependent tumor progression and lymphangiogenesis are up-regulated. Furthermore, single-cell transcriptomic analysis of LUAD clinical samples confirms a strong correlation between SOD3 expression in fibroblasts and characteristics of tumor exacerbation, such as lymphangiogenesis and metastasis. These findings underscore new insights into the role of CAF-derived SOD3 in LUAD progression and highlight its potential as a biomarker and therapeutic target.

Cerebral cavernous malformations (CCMs) are deemed to be acquired vascular anomalies that serve as a frequent driving force of a series of symptoms in central nervous system including hemorrhage, seizures and focal neurologic deficits, with an unknown etiology and no specific medication. For a long time, CCMs-associated studies mainly focus on investigating genetic mutations as well as vasculature-associated phenotypes. Notably, an increasing number of studies have recently revealed that inflammation and the heterogeneity of endothelial cells (ECs) play crucial roles in influencing the development of cavernomas, which ultimately exerts striking impacts on CCMs disease progression and patient outcomes. Interestingly, emerging single-cell RNA sequencing (scRNA-seq) technology has been validated to be essential for uncovering the molecular basis of multiple cell types involved in governing the development of CCMs disease. Herein, we comprehensively review recent advances in the applications of scRNA-seq technology in various CCMs models. Moreover, we concentrate on ECs, mural cells, fibroblasts, astrocytes as well as immune cells, predominantly exploring their unique transcriptional landscapes and contribution to the CCM pathologic progression. Finally, we summarize the therapies targeting these distinct cell populations in CCMs disease, aiming at identifying promising therapeutic strategies for retarding the development of CCMs.

Background

Ewing sarcoma (ES) is a rare but extremely aggressive bone and soft-tissue tumor. Clinical outcomes for patients with metastatic or recurrent ES remain poor, particularly for patients who are resistant to chemotherapy. This underscores an urgent need for alternative treatment strategies for these patients. A deep and comprehensive understanding of the cell–cell communications in ES may help identify new therapeutic approaches.

Methods

We first applied single-cell RNA sequencing (scRNA-seq) data analysis to map the cell–cell communication network within the ES tumor microenvironment (TME). Then, based on the cell–cell communication map, we inferred that multi-kinase anti-angiogenic inhibitors might effectively treat ES. Therefore, we investigated the anti-tumor efficacy of a novel multi-kinase inhibitor, KC1036, which primarily targets VEGFR2, MET, and AXL in ES cancer cell lines. The efficacy of KC1036 in ES was further validated in cell line-derived xenograft (CDX) models and a treatment-naïve patient-derived xenograft (PDX) model.

Results

We plotted a comprehensive cell–cell communication map of ES, where ES was characterized by highly immunosuppressive TME, strong autocrine signal NPY-NPY1R in tumor cells, wide activation of receptor kinase signaling pathways in cancer-associated fibroblasts (CAFs) (e.g., AXL, MET, FGFR, PDGFR, and KIT), and robust activation of tumor angiogenesis pathways (e.g., VEGFA/B-VEGFR1/2). Multi-kinase inhibitor KC1036 effectively inhibited ES tumor growth in both CDX and PDX models with superior efficacy compared to pazopanib, cabozantinib, and doxorubicin (DOX).

Conclusions

The novel anti-angiogenic inhibitor, KC1036, is effective in treating ES in the preclinical models.

Vascularization of implanted biomaterials is critical to reconstructive surgery and tissue engineering. Ultimately, the goal is to promote a rapidly perfusable hierarchical microvasculature that persists with time and can meet underlying tissue needs. We have previously shown that using a microsurgical technique, termed micropuncture (MP), in combination with porous granular hydrogel scaffolds (GHS) fabricated via interlinking hydrogel microparticles (microgels) results in a rapidly perfusable patterned microvasculature. However, whether this engineered microvasculature remains stable at longer time points remains unknown. Here, we combine MP with GHS and compare overall microvascular architecture and phenotype along with the evolving cellular landscape over a 28 day period. We demonstrate perfusable patterned microvascular stability in our MP + GHS model that occurs alongside a sustained rise in endothelial cell and macrophage recruitment. Specifically, MP yields a significant rise in M2 macrophages between the 7 and 28 day time points, suggesting ongoing microvascular remodeling, even in the presence of early pericyte stabilization. With time, the GHS microvasculature acquires a relatively equivalent arterial and venous morphology, as assessed through Ephrin-B2 and EphB4 quantification. Finally, angiography at 28 days shows that MP + GHS is associated with more perfusable microvascular loops when compared with MP + Bulk (nonporous) scaffolds. Hence, our surgically bioengineered microvasculature offers a unique opportunity to sustainably and precisely control biomaterial vascularization and ultimately advance the fields of reconstructive surgery and tissue engineering.

Limited vascularization and ischemia are major contributors to the chronicity of wounds, such as ulcers and traumatic injuries, which impose significant medical, social, and economic burdens. These challenges are particularly pronounced in patients with spinal cord injury (SCI), a disabling condition associated with vascular dysfunction, infections, and impaired peripheral circulation, complicating the treatment of pressure injuries (PIs) and the success of reconstructive procedures like grafts and flaps. Regenerative medicine aims to address these issues by identifying effective cellular therapies to restore vascular beds. Among these, cells from the stromal vascular fraction (SVF) of adipose tissue (AT) are promising due to their abundance of angiogenic and vasculogenic cells, including mesenchymal stem cells (MSCs) and endothelial colony-forming cells (ECFCs). This study evaluated the vasculogenic potential of AT-derived cellular fractions isolated via enzymatic digestion of white adipose tissue (WAT). We compared adipose-derived stem cells (ASCs) cultured from SVF with a combination of ECFCs and MSCs, expanded separately and transplanted in a 40:60 ratio. Results showed that while ASCs promote angiogenesis and vasculogenesis, the ECFC/MSC combination is superior, consistently forming perfused vascular beds in subcutaneous implants in nude mice. Furthermore, ECFCs and MSCs extracted from small amounts of WAT in SCI patients with PIs demonstrated similar functionality and vasculogenic potential to cells from healthy controls. These findings highlight the potential of AT-derived ECFCs and MSCs in autologous cell therapies, offering a promising avenue for advancing vascular regeneration in patients with SCI.