Wiring the Vascular Network with Neural Cues: A CNS Perspective

Abstract

The vascular and the nervous system are responsible for oxygen, nutrient, and information transfer and thereby constitute highly important communication systems in higher organisms. These functional similarities are reflected at the anatomical, cellular, and molecular levels, where common developmental principles and mutual crosstalks have evolved to coordinate their action. This resemblance of the two systems at different levels of complexity has been termed the "neurovascular link." Most of the evidence demonstrating neurovascular interactions derives from studies outside the CNS and from the CNS tissue of the retina. However, little is known about the specific properties of the neurovascular link in the brain. Here, we focus on regulatory effects of molecules involved in the neurovascular link on angiogenesis in the periphery and in the brain and distinguish between general and CNS-specific cues for angiogenesis. Moreover, we discuss the emerging molecular interactions of these angiogenic cues with the VEGF-VEGFR-Delta-like ligand 4 (Dll4)-Jagged-Notch pathway.

Nogo-A regulates vascular network architecture in the postnatal brain

“…Nogo-A deficiency does not disrupt the morphologic integrity of the newly formed vessel segments Angiogenesis involves various cellular and molecular sub-mechanisms such as vessel sprouting, branching, endothelial cell proliferation and migration, and finally lumen formation [1][2][3][4][5] that could be affected in a different proportion in Nogo-A-deficient animals. For example, increased vessel sprouting and branching would result in more vessel segments, enhanced endothelial cell proliferation and migration would lead to increased vessel length, and increased vessel proliferation or lumen formation would be associated with a bigger vessel diameter.…”

“…For example, increased vessel sprouting and branching would result in more vessel segments, enhanced endothelial cell proliferation and migration would lead to increased vessel length, and increased vessel proliferation or lumen formation would be associated with a bigger vessel diameter. 1,[3][4][5] In other words, a disproportional stimulation of angiogenesis could result in abnormal vessel morphology. 39,40 However, despite a significantly increased number of vessel branchpoints and vessel segments in Nogo-A À/À as compared to the control mice average branchpoint degree and other relevant characteristics of the 3D brain vessel network such as vessel diameter, vessel length, vessel tortuosity, and vessel volume were not affected in the Nogo-A transgenic animals.…”

“…4,5 During mouse brain development, vascularization of the CNS occurs in different steps: First, at embryonic day 7.5-8.5 (E7.5-E8.5), the perineural vascular plexus in the future meninges forms via vasculogenesis in the ventral region of the neural tube. 5,6 Then, at E9.5, sprouting angiogenesis from the perineural vascular plexus into the CNS tissue takes place.…”

“…4,14 Accordingly, the terms ''neurovascular link'' to describe the common principles of nerve and blood vessel growth as well as ''angioneurins'' to describe molecules regulating both systems have been introduced. 4,5 Whereas the effects of most of these axonal guidance molecules on angiogenesis and vascular patterning have been described outside the CNS and in the retina, only very little is known on whether these ''angioneurins'' affect postnatal brain angiogenesis and vascular network formation. 4,5 Nogo-A is a high molecular weight membrane protein with important inhibitory functions for neurite growth in the adult CNS, where it limits the regeneration of neurons after spinal cord injury or stroke and dampens synaptic plasticity.…”

WITHDRAWN: Endothelial Nogo-B suppresses cancer cell proliferation via a paracrine TGF-β/Smad signaling

“…In this study, we examined Nogo-B expression in vascular endothelial cells in HCC tissues from patients and investigated the role of endothelial Nogo-B in HCC growth. In addition, recent studies have provided evidence suggesting that neurovascular crosstalk was pretty important for certain neurological diseases [16,17]. Here, we also explored the role of endothelial Nogo-B in cancer progression.…”