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Sensory neurons directly promote angiogenesis in response to inflammation via substance P signaling
Author(s) -
Liu Lingjia,
Dana Reza,
Yin Jia
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201903236r
Subject(s) - angiogenesis , cornea , substance p , neurogenic inflammation , inflammation , neovascularization , proinflammatory cytokine , in vivo , microbiology and biotechnology , sensory nerve , sensory system , trigeminal ganglion , neuropeptide , biology , chemistry , immunology , receptor , neuroscience , medicine , cancer research
Blood vessels and nerves travel together to supply most tissues in the body. 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‐basal and epithelial nerve densities in the cornea were reduced in dry eye disease (DED). We established a co‐culture 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‐1, 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.