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However, there is a knowledge gap in the mechanisms underlying the direct regulation of angiogenesis by nerves. In the current study, we examined the regulation of angiogenesis by sensory nerves in response to inflammation using the cornea, a normally avascular and densely innervated ocular tissue, as a model. We used desiccating stress as an inflammatory stimulus in vivo and found that sub\u2010basal and epithelial nerve densities in the cornea were reduced in dry eye disease (DED). We established a co\u2010culture system of trigeminal ganglion sensory neurons and vascular endothelial cells (VEC) and found that neurons isolated from mice with DED directly promoted VEC proliferation and tube formation compared with normal controls. In addition, these neurons expressed and secreted higher levels of substance P (SP), a proinflammatory neuropeptide. SP potently promoted VEC activation in vitro and blockade of SP signaling with spantide I, an antagonist of SP receptor Neurokinin\u20101, significantly reduced corneal neovascularization in vivo. Spantide I and siRNA knockdown of SP abolished the promotion of VEC activation by DED neurons in vitro. Taken together, our data suggested that sensory neurons directly promote angiogenesis via SP signaling in response to inflammation in the cornea.<\/jats:p>","DOI":"10.1096\/fj.201903236r","type":"journal-article","created":{"date-parts":[[2020,3,12]],"date-time":"2020-03-12T06:34:55Z","timestamp":1583994895000},"page":"6229-6243","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":62,"title":["Sensory neurons directly promote angiogenesis in response to inflammation via substance P signaling"],"prefix":"10.1096","volume":"34","author":[{"given":"Lingjia","family":"Liu","sequence":"first","affiliation":[{"name":"Schepens Eye Research Institute of Massachusetts Eye and Ear Harvard Medical School Boston MA USA"},{"name":"School of Medicine Nankai University Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reza","family":"Dana","sequence":"additional","affiliation":[{"name":"Schepens Eye Research 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