Elevated levels of IL-8 have been detected in the vitreous samples of patients with diabetic retinopathy. However, its role in retinal neovascularization remains unknown. We hypothesized that IL-8 and its murine orthologues, CXCL1/2, are key mediators of oxygen-induced retinopathy (OIR)-driven retinal angiogenesis. To this end, we found that VEGFA stimulates CXCL1/2 and their receptor CXCR2 expression in mouse retinal microvascular endothelial cells (MRMVECs) in a time-dependent manner. Recombinant CXCL1/2 induced MRMVEC migration, proliferation, sprouting, and tube formation alone and in combination. Neutralizing CXCL1/2 or CXCR2 antibodies (Abs) attenuated the angiogenic effects of CXCL1/2 as well as VEGFA. In line with these observations in mice, VEGFA induced IL-8 and its receptor CXCR2 expression in human retinal microvascular endothelial cells (HRMVECs), and neutralizing IL-8 or CXCR2 Abs suppressed their angiogenic effects. Furthermore, OIR induced CXCL1/2 and CXCR2 expression in the mouse retina in vivo, and blockade of their function using their neutralizing Abs reduced retinal neovascularization. Mechanistically, depletion of ATF6 or GRP78 levels abrogated VEGFA-induced CXCL1/2 and CXCR2 expression in MRMVECs and IL-8 and CXCR2 expression in HRMVECs in vitro and OIR-induced CXCL1/2 and CXCR2 expression in vivo in mice. Furthermore, silencing VEGFR2 or VEGFR3 levels inhibited VEGFA/OIR-induced ATF6-GRP78 activation and their downstream CXCL1/2, IL-8 and CXCR2 expression both in vitro and in vivo. Together, these findings identify IL-8 as potential therapeutic target for treating retinal neovascular diseases.
Endothelial colony-forming cells (ECFCs) are endothelial progenitor cells characterized by robust proliferative and vasculogenic capacities, making them promising candidates for therapeutic tissue revascularization. However, the clinical application of ECFCs is hindered by their functional impairment under pathological conditions, such as diabetes and cardiovascular disease. Accumulating evidence indicates that aberrant epigenetic modifications, including DNA methylation, histone modifications, and non-coding RNA-mediated regulation, have been implicated in disease-associated ECFC dysfunction. In this review, we summarize current insights into the epigenetic regulation of ECFCs in pathological contexts, discuss epigenetic intervention strategies aimed at restoring ECFC function, and further highlight the therapeutic potential of ECFC-derived extracellular vesicles (EVs) as carriers of epigenetic cargo that promotes vascular repair. Collectively, a deeper understanding of the epigenetic landscape of ECFCs and ECFC-derived EVs may facilitate the development of novel therapeutic approaches for vascular regeneration and accelerate the clinical translation of ECFC- and EV-based therapies.
Sex differences in adipose tissue vascular remodeling critically influence susceptibility to obesity-associated metabolic disease, yet the underlying mechanisms remain unclear. Here we identify Forkhead box O1 (FoxO1) as a sex-dependent regulator of endothelial function, with female endothelial cells (EC) expressing higher levels of FoxO1 and depending on it to maintain vascular remodeling and metabolic homeostasis. Accordingly, FoxO1 loss in females disrupted angiogenesis, and promoted adipocyte hypertrophy, weight gain and glucose dysregulation, whereas opposite effects have been reported in males. This phenotype was associated with a shift in the endothelial transcriptome toward a male-like state, consistent with loss of female protection against diet-induced metabolic dysfunction. Mechanistically, FoxO1 inhibition exerted time-dependent effects, with short-term suppression promoting proliferation and sustained inhibition reducing proliferation and inducing metabolic dysfunction. Although also observed in males, these effects were more pronounced in female EC, which also selectively exhibited mitochondrial dysfunction, increased oxidative stress and DNA damage accumulation, culminating in a senescence-like arrest. Antioxidant treatment partially rescued this phenotype, implicating oxidative stress as a driver of female-specific vulnerability. These findings reveal a sex-dependent divergence in FoxO1 function and identify endothelial FoxO1 as a determinant of opposing vascular and metabolic responses to obesogenic stress.
It is with great pleasure that we announce the new journal impact factor for Angiogenesis: 11.2. This milestone reflects the vitality of our field and the extraordinary quality of the research our authors continue to entrust to us. Angiogenesis remains the premier international, peer-reviewed journal devoted to the cellular and molecular mechanisms that govern blood vessel formation in health and disease, and this new metric confirms what we have long believed: the science of vascular biology has never been more central to biomedicine.
