Long Jennifer B, Jay Steven M, Segal Steven S, Madri Joseph A
Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut, USA.
Dev Biol. 2009 Oct 1;334(1):119-32. doi: 10.1016/j.ydbio.2009.07.023. Epub 2009 Jul 23.
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.
交感神经活动通过改变外周血管阻力来调节血压。血管交感神经支配的变化表明，血管衍生的信号在发育过程中促进特定血管的选择性神经支配。当轴突向外周靶点延伸时，它们沿着动脉网络，跟随引导信号的梯度迁移。这些梯度的综合比例可能决定轴突是否朝着血管生长并支配血管，还是越过未受神经支配的血管继续向外周靶点生长。利用三维（3D）共培养中定向的神经突生长，我们观察到，与未受神经支配的血管相比，颈上神经节外植体（SCG）向受神经支配的血管的轴突生长增加，这部分是由血管内皮生长因子（VEGF-A）和Semaphorin3A（Sema3A）介导的，它们都通过神经纤毛蛋白-1（Nrp1）发出信号。由高表达VEGF-A-LacZ的血管或rhVEGF-A/藻酸盐球递送的外源性VEGF-A增加了交感神经突的生长，而外源性rhSema3A/Fc则减少了神经突的生长。在所检查的受神经支配和未受神经支配的血管之间，VEGF-A的表达相似。Sema3A在未受神经支配的血管中表达较高。Sema3A和VEGF-A的空间梯度可能促进Nrp1的差异性结合。高表达Sema3A的血管有利于Nrp1-PlexinA1信号传导，产生化学排斥信号，限制交感神经突的生长和血管神经支配；而低表达Sema3A的血管有利于Nrp1-VEGFR2信号传导，为交感神经突的生长和血管神经支配提供化学吸引信号。
