Heterogeneous proper t i es of vascular endothelial cells in the brain:The brain displays large energy dynamics and consumption,and this high level of metabolic demands is fulfilled by a continuous supply of glucose and oxygen through its vascular networks.Brain vasculature consists of highly divergent blood vessel branches,giving rise to a dense network of capillaries that supply blood to all cells across the brain.This elaborated vascular network is thought to develop via angiogenesis,a process in which new blood vessels grow from pre-existing vasculature.Brain capillaries exhibit organotypic features distinct from other tissues and are formed primarily by two major endothelial cell(EC)types:those that form the semi-permeable blood-brain barrier(BBB)and those that develop highly permeable pores known as fenestrae(Matsuoka et al.,2022).The structural and functional differences between BBB and fenestrated vascular ECs represent a fundamental feature of brain vasculature and form the foundation for both brain function and homeostasis.
After brain damage,regenerative angiogenesis and neurogenesis have been shown to occur simultaneously in mammals,suggesting a close link between these processes.However,the mechanisms by which these processes interact are not well understood.In this work,we aimed to study the correlation between angiogenesis and neurogenesis after a telencephalic stab wound injury.To this end,we used zebrafish as a relevant model of neuroplasticity and brain repair mechanisms.First,using the Tg(fli1:EGFP×mpeg1.1:mCherry)zebrafish line,which enables visualization of blood vessels and microglia respectively,we analyzed regenerative angiogenesis from 1 to 21 days post-lesion.In parallel,we monitored brain cell proliferation in neurogenic niches localized in the ventricular zone by using immunohistochemistry.We found that after brain damage,the blood vessel area and width as well as expression of the fli1 transgene and vascular endothelial growth factor(vegfaa and vegfbb)were increased.At the same time,neural stem cell proliferation was also increased,peaking between 3 and 5 days post-lesion in a manner similar to angiogenesis,along with the recruitment of microglia.Then,through pharmacological manipulation by injecting an anti-angiogenic drug(Tivozanib)or Vegf at the lesion site,we demonstrated that blocking or activating Vegf signaling modulated both angiogenic and neurogenic processes,as well as microglial recruitment.Finally,we showed that inhibition of microglia by clodronate-containing liposome injection or dexamethasone treatment impairs regenerative neurogenesis,as previously described,as well as injury-induced angiogenesis.In conclusion,we have described regenerative angiogenesis in zebrafish for the first time and have highlighted the role of inflammation in this process.In addition,we have shown that both angiogenesis and neurogenesis are involved in brain repair and that microglia and inflammation-dependent mechanisms activated by Vegf signaling are important contributors to these processes.This study paves the way for a
Anti-angiogenic drugs(AADs),which mainly target the vascular endothelial growth factor-A signaling pathway,have become a therapeutic option for cancer patients for two decades.During this period,tremendous clinical experience of anti-angiogenic therapy has been acquired,new AADs have been developed,and the clinical indications for AAD treatment of various cancers have been expanded using monotherapy and combination therapy.However,improvements in the therapeutic outcomes of clinically available AADs and the development of more effective next-generation AADs are still urgently required.This review aims to provide historical and perspective views on tumor angiogenesis to allow readers to gain mechanistic insights and learn new therapeutic development.We revisit the history of concept initiation and AAD discovery,and summarize the up-to-date clinical translation of anti-angiogenic cancer therapy in this field.
Ziheng GuoXu JingXiaoting SunShishuo SunYunlong YangYihai Cao
Angiogenesis,the process of formation of new capillaries from existing blood vessels,is required for multiple physiological and pathological processes.Complement factorH(CFH)is a plasma protein that inhibits the alternative pathway of the complement system.Loss of CFH enhances the alternative pathway and increases complement activation fragments with pro-angiogenic capacity,including complement 3a,complement 5a,and membrane attack complex.CFH protein contains binding sites for C-reactive protein,malondialdehyde,and endothelial heparan sulfates.Dysfunction of CFH prevents its interaction with these molecules and initiates pro-angiogenic events.Mutations in the CFH gene have been found in patients with age-related macular degeneration characterized by choroidal neovascularization.The Cfh-deficient mice show an increase in angiogenesis,which is decreased by administration of recombinant CFH protein.In this review,we summarize the molecular mechanisms of the anti-angiogenic effects of CFH and the regulatory mechanisms of CFH expression.The therapeutic potential of recombinant CFH protein in angiogenesisrelated diseases has also been discussed.
Jiang LiKaili WangMaria N.StarodubtsevaEldar NadyrovCarolyn M.KapronJosephine HohJu Liu
A decline in mucosal vascularity is a histological hallmark of oral submucous fibrosis (OSF), a premalignant disease that is largely induced by betel quid chewing. However, the lack of available models has challenged studies of angiogenesis in OSF. Here, we found that the expression of thrombospondin 1 (THBS1), an endogenous angiostatic protein, was elevated in the stroma of tissues with OSF. Using a fibroblast-attached organoid (FAO) model, the overexpression of THBS1 in OSF was stably recapitulated in vitro. In the FAO model,treatment with arecoline, a major pathogenic component in areca nuts, enhanced the secretion of transforming growth factor (TGF)-β1 by epithelial cells, which then promoted the expression of THBS1 in fibroblasts. Furthermore, human umbilical vein endothelial cells (HUVECs)were incorporated into the FAO to mimic the vascularized component. Overexpression of THBS1 in fibroblasts drastically suppressed the sprouting ability of endothelial cells in vascularized FAOs (v FAOs). Consistently, treatment with arecoline reduced the expression of CD31in v FAOs, and this effect was attenuated when the endothelial cells were preincubated with neutralizing antibody of CD36, a receptor of THBS1. Finally, in an arecoline-induced rat OSF model, THBS1 inhibition alleviated collagen deposition and the decline in vascularity in vivo. Overall, we exploited an assembled organoid model to study OSF pathogenesis and provide a rationale for targeting THBS1.
