Remodeling vasculature to avoid blindness

doi:10.1126/science.abd7063

GSTDTAP > 气候变化

DOI	10.1126/science.abd7063
	Remodeling vasculature to avoid blindness
	Eugene A. Podrez; Tatiana V. Byzova
	2020-08-21
发表期刊	Science
出版年	2020
英文摘要	Vascular remodeling is essential for building hierarchically structured vascular networks, which in turn support proper organ function ([ 1 ][1]). The retina is particularly dependent on optimal blood supply, and insufficient or excessive vasculature often leads to blindness. The process of vascular regression reduces blood vessel density, facilitating normalization of vasculature and subsequent tissue repair ([ 2 ][2]). Regression is either caused by the withdrawal of essential vascular growth factors or by triggering endothelial apoptosis and subsequent pruning of vasculature ([ 3 ][3]). However, it is unknown how dysfunctional and excessive retinal blood vessels are selected and marked for pruning. On page 934 of this issue, Binet et al. ([ 4 ][4]) reveal that pathological vasculature in the retina of mice and humans orchestrates its own remodeling by promoting the extrusion of neutrophil extracellular traps (NETs). This mechanism might be applied to other pathologies that require vascular remodeling, such as cancer, pulmonary hypertension, and heart disease ([ 3 ][3]). Retinal ischemic diseases, such as retinopathy of prematurity and diabetic retinopathy, are triggered by insufficient vasculature, leading to ischemia (lack of oxygen), which is compensated for by excessive production of vascular growth factors, primarily vascular endothelial growth factor (VEGF). This leads to overgrowth of misdirected and leaky vasculature, with signs of vascular deterioration and senescence (in which cells stop dividing and become dysfunctional) stimulated by aging or stress, similar to processes observed in tumors ([ 3 ][3]). Regression of this excessive and pathological vasculature is a necessary step to avoid chronic inflammation and to ensure tissue repair. Thus, a precise understanding of the exact molecular mechanisms governing vascular regression in retinal and other diseases is of the utmost clinical importance. Using high-resolution droplet-based RNA sequencing and sophisticated bioinformatics approaches in animal models of retinopathy, Binet et al. were able to effectively tease out the main players of vascular regression at the molecular, cellular, and tissue levels. They showed in mice and humans that the entire process relies on the innate immune system, namely neutrophils, which are deployed during the late phase of retinal disease, which is associated with vascular regression rather than vascular growth. Neutrophils serve as a first line of innate immunity against pathogens by means of oxidative burst, phagocytosis, and release of weblike DNA and protein structures called NETs. Besides their originally defined role in pathogen defense ([ 5 ][5]), NETs also mediate severe inflammatory reactions of primarily a destructive nature, such as cancer metastasis and tissue and organ damage within the vascular, pulmonary, and renal systems ([ 6 ][6]). Most recently, NETs have been implicated in organ damage and other complications of coronavirus disease 2019 (COVID-19) ([ 7 ][7]). Binet et al. show that during the process of retinal vascular repair, NETs perform a very different function of marking senescent vascular branches for pruning (see the figure). Under different circumstances, this tagging for destruction might lead to impaired blood supply and eventually to organ failure; however, in ischemic retinopathy, this process serves an essential prerequisite for tissue repair. It remains to be determined whether this role of NETs is restricted only to tissues of primarily postmitotic nature, such as the retina and central nervous system, or whether it also operates in other pathologies, such as neoplasms, or even whether it might underlie developmental vascular restructuring. Involvement of NETs in other pathologies seems to be likely because NETosis is stimulated by a specific combination of factors, including interleukin-1β (IL-1β) and C-X-C motif chemokine 1 (CXCL1), which are secreted by senescent cells and found not only in aging but also during development ([ 8 ][8]) and in actively growing tissues such as tumors ([ 9 ][9]). In diseased retinas, this senescence-associated secretory phenotype (SASP) is observed in endothelial cells, pericytes, astrocytes, and Müller glia but not in retinal ganglion cells (which connect photosensitive cells in the retina to the optic nerve), which are also known to undergo senescence. Together, these findings indicate that various types of senescent cells might be able to attract neutrophils and deploy NETs. It will be interesting to explore why only certain types of senescent cells promote NETs. ![Figure][10] Vascular senescence facilitates tissue repair Dysfunctional senescent retinal vasculature produces senescence-associated secretory phenotype (SASP) components, attracts neutrophils, and stimulates the extrusion of neutrophil extracellular traps (NETosis, see photo below). This causes endothelial cell apoptosis and vascular pruning, which is essential for vascular repair and tissue recovery in ischemic retinopathy. CREDIT: ADAPTED FROM T. V. BYZOVA BY MELISSA THOMAS BAUM/ SCIENCE Acquisition of a SASP signature is believed to be mainly detrimental because of its contribution to inflammation, oxidative stress, thrombosis (blood clotting), and metabolic imbalance ([ 10 ][11]). In endothelium, the SASP signature includes proangiogenic factors that promote vascularization in tumors ([ 9 ][9]) and in age-related diseases, including retinopathy ([ 11 ][12]). In tumors, SASP facilitates drug delivery, thus making tumors vulnerable to chemotherapy ([ 9 ][9]). In proliferative diabetic retinopathy, however, SASP cytokines such as IL-6, IL-8, and VEGF directly promote pathological vascular growth, delaying tissue repair ([ 11 ][12]). However, similar to Binet et al. , studies found beneficial roles of SASP in tissue growth ([ 8 ][8]) and wound healing ([ 12 ][13]) as inducers of stem-like characteristics of keratinocytes, driving epithelial regeneration ([ 13 ][14]). It is notable that the retinal vasculature activates a “self-correcting” program by acquiring the SASP. Binet et al. demonstrate that the SASP signature is associated with activation of RAS pathways within a population of senescent retinal endothelial cells. In cancer, proangiogenic SASP components are the result of inhibition rather than activation of the KRAS pathway ([ 9 ][9]). Nevertheless, even in cancer, SASP promotes therapeutically beneficial vascular remodeling. Together, these results support the concept that cellular senescence has substantial value as a therapeutic target in a variety of disorders associated with vascular dysfunction, and that induction of vascular senescence is a prerequisite for vascular remodeling and optimization. Moreover, because most of the vasculature requires active and uninterrupted maintenance, this senescence-induced regression and remodeling aided by neutrophils might also be applicable to vascular homeostasis. 1. [↵][15]1. A. R. Pries, 2. T. W. Secomb , Physiol. 29, 446 (2014). [OpenUrl][16] 2. [↵][17]1. E. C. Watson, 2. Z. L. Grant, 3. L. Coultas , Cell. Mol. Life Sci. 74, 4387 (2017). [OpenUrl][18] 3. [↵][19]1. C. Korn, 2. H. G. Augustin , Dev. Cell 34, 5 (2015). 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[OpenUrl][52][Abstract/FREE Full Text][53] Acknowledgments: The authors are supported by National Institutes of Health (HL142772 and HL145536). 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领域	气候变化 ; 资源环境
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文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/291205
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Eugene A. Podrez,Tatiana V. Byzova. Remodeling vasculature to avoid blindness[J]. Science,2020.
APA	Eugene A. Podrez,&Tatiana V. Byzova.(2020).Remodeling vasculature to avoid blindness.Science.
MLA	Eugene A. Podrez,et al."Remodeling vasculature to avoid blindness".Science (2020).