Sensory neurons directly promote angiogenesis in response to inflammation via substance P signaling

Abstract

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.

The Role of Neuropeptides in Pathogenesis of Dry Eye

“…Recently, several preclinical studies have reported using a dry eye animal model to elucidate the roles of neuropeptide/neuropeptide-specific receptors in the pathogenesis of DED ( Table 3 ). There have been reports that the expression of SP is elevated in the cornea, conjunctiva, and trigeminal ganglion by exposure to DS in the controlled-environment chamber (CEC) [ 218 , 219 , 220 ]. Yu et al [ 218 ] investigated the expression of SP at the ocular surface and evaluated its effect on the maturation of APCs, the key cells involved in the induction of the Th17-mediated response in DED.…”

“…Taketani et al [ 220 ] showed that a significant increase in SP levels promotes Treg dysfunction in DED, and blockade of SP effectively restores Treg function and alleviates DED severity. Additionally, Liu et al [ 219 ] investigated the regulation of angiogenesis by sensory nerves in response to DS using a coculture system of vascular endothelial cells and trigeminal ganglion sensory neurons harvested from DED mice. SP potently promoted the activation of the vascular endothelial cells in vitro, and blockade of SP signaling with spantide I, an antagonist of NK1R, significantly reduced corneal neovascularization in vivo, suggesting that sensory neurons directly promote angiogenesis via SP signaling in response to inflammation in the cornea.…”

“…Difficulty in performing in vitro studies using neuronal cell culture is another hurdle for the research that might reveal direct interactions between neuronal systems and immunologic systems. Recently, the trigeminal neuronal primary culture technique was used in some studies related to DED pathogenesis [ 218 , 219 ]. However, considering the possibility that the cells were in a slightly inflamed state due to trauma associated with the dissection performed to isolate the cells and their limited life span (typically days to weeks) [ 250 , 251 ], the in vitro primary neuronal cell culture model is limited for revealing the exact pathways in the pathogenesis of DED.…”

A Hypothalamic-Controlled Neural Reflex Promotes Corneal Inflammation

“… 10 More recently, it has been reported that sensory neurons directly promote angiogenesis via SP signaling in response to corneal inflammation. 41 …”

Neural regulations of the tumor microenvironment

“… 89 Sensory nerves that travel alongside blood vessels promote angiogenesis via substance P mediated signaling during inflammation. 89 , 90 A similar neuronal‐mediated process promoting angiogenesis appears to function in the TME. Adrenergic nerves in the TME release norepinephrine triggering an angiogenic switch by signaling through the ADRB2 on endothelial cells, thereby promoting increased vascularization of the TME.…”