, 2010 and Wang et al., 2010b). The neurovascular link is bidirectional and molecules originally discovered as angiogenic molecules also have roles in establishing the connectivity of the nervous system—they have been termed “angioneurins” (Zacchigna et al., 2008). One of the best-known examples is VEGF, which regulates neuronal cell migration (Ruiz de Almodovar et al., 2009), axon guidance (Erskine et al., 2011 and Ruiz de Almodovar et al., 2011), turning of leading processes of migrating cerebellar neurons (Ruiz de Almodovar et al., 2010), and dendritogenesis (Licht et al.,

2010). VEGF-D, another member of the VEGF family, controls the length and complexity of dendrites in hippocampal neurons and regulates memory formation Cabozantinib mw (Mauceri et al., 2011). Moreover, D. melanogaster and C. elegans lacking an elaborate vascular network express an ancestral VEGF variant that affects nervous development ( Zacchigna et al., 2008). Sema3E stimulates axon elongation via binding to a Plexin-D1/Nrp1 complex with subsequent VEGFR2 activation ( Bellon et al., 2010). Other “angioneurins” include members of the TGFβ1, Shh, Wnts, BMPs, FGFs, and other families ( Zacchigna et al., 2008). An intriguing question is whether hypoxia,

a proangiogenic stimulus, regulates CNS wiring. Initial support heretofore is provided by genetic studies in C. elegans. When challenged by low oxygen, this invertebrate mounts a protective organismal survival response by upregulating the Eph-receptor PF-06463922 cell line VAB-1,

a repulsive guidance receptor in the CNS; the price to pay for the protection is that axon pathfinding is perturbed ( Pocock and Hobert, 2008). Hypoxia also activates circuits for processing sensory information, underscoring that oxygen levels influence CNS wiring ( Pocock and Hobert, 2010). Another example of the neurovascular link is the coalignment of vessels and nerves, with nerves guiding vessels tracking alongside nerves, and vice versa. For instance, neural crest cells (NCCs) give rise to autonomic nerves that innervate SMCs of peripheral resistance arteries (Ruhrberg Vasopressin Receptor and Schwarz, 2010). These autonomic nerves regulate contractility and tissue perfusion. Resistance arteries attract their own innervation by secreting guidance cues for sympathetic neurons including VEGF, artemin, NT-3, and endothelin-3 (Ruiz de Almodovar et al., 2009). Besides its role in establishing the autonomic innervation, VEGF remains necessary for the maintenance of this autonomic nervous network in adulthood. Reduced production of VEGF by SMCs in VEGF-hypomorph VEGF∂/∂ mice renders periarterial autonomic nerves dysfunctional (Storkebaum et al., 2010). Pial arteries also possess (para)sympathetic and sensory-motor perivascular nerves that originate from peripheral ganglia, referred to as “extrinsic” innervation, but little is known about the molecules regulating the development and maintenance of these nerves. In the other direction, axons guide vessels to cotrack along them.