Angiogenesis最新文献

Deleterious mutations in the GDF2 gene, encoding BMP9, are causative of pulmonary arterial hypertension and hereditary haemorrhagic telangiectasia. Paradoxically, BMP9 germ-line knockout (Gdf2^−/−; Bmp9 KO) and double Bmp9 KO/conditional Bmp10 cKO (dKO) mice exhibit an attenuated response to PAH-inducing stimuli. We asked whether this contradiction is due to the pathological, physiological, or genetic consequences of BMP9 knockout. In Bmp9 KO mice we observed reduced pulmonary vascular smooth muscle cell (SMC) coverage and using RNA-seq analysis of Bmp9 KO mouse lungs identified two novel genes, COLQ and ITGA6, which were differentially regulated in a human PAH RNA-seq dataset. In order to study BMP10 loss, postnatal tamoxifen treatment was required to induce Bmp10 cKO. As previously reported, in dKO mice we observed cardiomegaly and splenomegaly, as well as hyperplasia and hemosiderosis in the pulmonary vasculature. Surprisingly, tamoxifen treated Bmp9 KO control mice phenocopied these pathological changes in dKO mice and downregulated SMC marker gene transcription. Loss of BMP10 is not critical for severe tissue remodelling in the lung, heart, and spleen, rather Bmp9 KO mice appear sensitive to tamoxifen and BMP9 loss is the primary cause of mild vessel remodelling due to a basal reduction of smooth muscle cell coverage. This study suggests that interaction of the BMP pathway with tamoxifen needs to be carefully considered when studying Bmp9 KO mice and urges caution in the context of tamoxifen use when studying cardiovascular and pulmonary disease models.

Quaking (QKI), a member of the signal transduction and activators of RNA (STAR) family of RNA-binding proteins, affects a wide range of functions, including alternative splicing, mRNA precursor processing, mRNA transport and localization, mRNA stabilization, and translation. Recently, QKI has been found to have critical roles in vasculogenesis and angiogenesis due to its effects on alternate splicing and other post-transcriptional modifications involving small RNAs in the endothelial cells (ECs). Aberrant expression or mutation of QKI in ECs can result in pro- or anti-angiogenic effects under different physiological and pathological conditions, including tumor angiogenesis. However, the regulatory roles of QKI in EC biology remain poorly described. This review summarizes our current understanding of the QKI isoforms and their functions in ECs, as well as the potential utility of QKI as an emerging translational target for angiogenic-based therapies.

Microvascular network formation is governed by a variety of factors, with interstitial flow (IF) playing a pivotal role. However, the impact of multidirectional IF (MDIF) on microvascular network development remains insufficiently explored. In this study, we developed a platform consisting of a Square chip capable of generating MDIF and a deep learning-based Vasculature-on-a-Chip Analysis Tool (VoCAT) for high-efficient analysis of vascular morphology on the chip. Using this platform, we demonstrated that microvascular networks formed on the Square chip exhibited intricate structural features with enhanced functionality. We also demonstrated its utility in modeling a tumor microenvironment with complex microvascular networks and observed enhanced tumor cell migration. This study provides the first evidence that MDIF promotes microvascular network formation, offering new perspectives for advanced in vitro vascular and disease research.

Diabetic retinopathy (DR) is characterized by chronic retinal inflammation and vascular remodeling that can threaten vision. Most current treatments are administered intravitreally and target vascular endothelial growth factor A (VEGF) but are often ineffective. Nevertheless, few alternative treatments, and no oral DR therapies, exist. Although IL-1β, TNFα, and IL-8 are upregulated along with VEGF within eyes with DR, they are not therapeutically targeted. IL-8 levels correlate with DR progression and resistance to anti-VEGF therapy, suggesting VEGF-independent contributions of IL-8-receptor signaling to DR. IL-1β and TNFα, in turn, enhance expression of pro-angiogenic CXCR2 ligands (e.g. IL-8, CXCL1) in human Müller cells (hMC). Despite investigation of CXCR2 roles in several angiogenic and fibrotic diseases, CXCR2 inhibitors have not been explored in DR models. In this study, we show protein upregulation of IL-8 and CXCL1, but no detectable VEGF in conditioned media (CM) from IL-1β and TNFα-stimulated hMC. Stimulation of human retinal microvascular endothelial cells (hRMEC) with this human Müller cell-conditioned media (hMC-CM), as well as directly with IL-8, upregulated hRMEC proliferation and migration. CXCR2 inhibition reduced pro-angiogenic hRMEC responses to hMC-CM and IL-8. Likewise, in vivo, in the oxygen-induced retinopathy (OIR) model, either genetic (Cxcr2^-/-) or pharmacologic (SB225002) CXCR2 inhibition reduced pre-retinal neovascularization without altering avascularity or VEGF expression. These findings suggest that: (a) Müller cells may link inflammatory and angiogenic responses in the retina, (b) CXCR2 activation may contribute to DR, and (c) CXCR2 inhibitors may be repurposed to reduce pre-retinal neovascularization, a key feature of proliferative DR.

This letter aims to provide a forward-looking analysis of the recent preclinical study by Ou et al. (Angiogenesis, 2025) on the efficacy of the multi-kinase inhibitor KC1036 in Ewing sarcoma (ES).We conducted a critical appraisal of the reported data, focusing on the dual anti-angiogenic and direct anti-tumor mechanisms of KC1036. The analysis is contextualized within the current understanding of ES pathogenesis and treatment resistance.The original study compellingly demonstrates that KC1036, by concurrently inhibiting VEGFR and FGFR signaling, effectively suppresses ES growth. While these findings are promising, they raise pivotal questions for future investigation. Key considerations include the precise mechanistic interplay between KC1036 and the EWSR1-FLI1 oncogenic driver, the potential evolution of resistance despite multi-targeted inhibition, and the critical assessment of the agent’s therapeutic index.KC1036 represents a rational and potent therapeutic candidate for ES. The primary challenges ahead lie in delineating its molecular mechanisms of action beyond angiogenesis, prospectively defining resistance pathways to guide combination therapies, and rigorously evaluating its safety profile to ensure successful clinical translation. This letter outlines these priorities to stimulate further research.

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.