VEGF-A and Semaphorin3A: Modulators of vascular sympathetic innervation

Abstract

Sympathetic nerve activity regulates blood pressure by altering peripheral vascular resistance. Variations in vascular sympathetic innervation suggest that vascular-derived cues promote selective innervation of particular vessels during development. As axons extend towards peripheral targets, they migrate along arterial networks following gradients of guidance cues. Collective ratios of these gradients may determine whether axons grow towards and innervate vessels or continue past non-innervated vessels towards peripheral targets. Utilizing directed neurite outgrowth in a three-dimensional (3D) co-culture, we observed increased axon growth from superior cervical ganglion explants (SCG) towards innervated compared to non-innervated vessels, mediated in part by vascular endothelial growth factor (VEGF-A) and Semaphorin3A (Sema3A) which both signal via neuropilin-1 (Nrp1). Exogenous VEGF-A, delivered by high-expressing VEGF-A–LacZ vessels or by rhVEGF-A/alginate spheres, increased sympathetic neurite outgrowth while exogenous rhSema3A/Fc decreased neurite outgrowth. VEGF-A expression is similar between the innervated and non-innervated vessels examined. Sema3A expression is higher in non-innervated vessels. Spatial gradients of Sema3A and VEGF-A may promote differential Nrp1 binding. Vessels expressing high levels of Sema3A favor Nrp1-PlexinA1 signaling, producing chemorepulsive cues limiting sympathetic neurite outgrowth and vascular innervation; while low Sema3A expressing vessels favor Nrp1-VEGFR2 signaling providing chemoattractive cues for sympathetic neurite outgrowth and vascular innervation.

Proangiogenic features in chronic pelvic pain caused by adenomyosis

“…It is also a mitogen for astroglia and Schwann cells in vitro [3,16]. Studies have shown that exogenous VEGF-A increases the number of processes of the sympathetic ganglia in explants [17] and promotes the growth of sympathetic axons from surgically denervated adult rats [18]. VEGF-A promotes the growth of axons, independently from its vascular role, through two receptors: either VEGFR2 [19] or neuropilin-1 (NRP1) [20].…”

Netrin-1 controls sympathetic arterial innervation

“…Netrin-1 was not expressed in the heart, and cardiac innervation was normal in Ntn1 mutants. Interestingly, a growing body of evidence indicates that innervation of the heart and large arteries is regulated by other molecules, including NGF and the axon guidance molecule Sema3A and its receptor Nrp1 (41)(42)(43). Therefore, sympathetic innervation of cardiovascular targets may be regulated by specific combinations of guidance molecules: Sema3A/Nrp1 for the heart and large arteries and netrin/DCC for resistance arteries.…”

Diverse roles for VEGF-A in the nervous system

“…Thus, exogenous VEGF-A increases neurite outgrowth from sympathetic ganglion explants (Long et al, 2009) and promotes sympathetic axon growth for re-innervation of surgically denervated femoral arteries in adult rats (Marko and Damon, 2008). VEGF-A also promotes the sympathetic regulation of resistance arteries, as their constriction is reduced in response to cold stress in Vegfa delta/delta mice with low levels of endogenous VEGF-A (Storkebaum et al, 2010).…”