Beyond vessels: unraveling the impact of VEGFs on neuronal functions and structure

 Your competent? doctor wasn't competent enough to write a protocol on this in the last 14 years? My God, the fucking stupidity in stroke is off the charts!

Send me hate mail on this: oc1dean@gmail.com. I'll print your complete statement with your name and my response in my blog. Or are you afraid to engage with my stroke-addled mind? No excuses are allowed! You're medically trained; it should be simple to precisely refute all my points with NO EXCUSES!! Your definition of competence in stroke is obviously much lower than stroke survivors' definition of your competence! Swearing at me is allowed, I'll return the favor. Don't even attempt to use the excuse that brain research is hard.

VEGF (57 posts to April 2011)

Beyond vessels: unraveling the impact of VEGFs on neuronal functions and structure

• Bahar Aksan &
• Daniela Mauceri 

Journal of Biomedical Science volume 32, Article number: 33 (2025) Cite this article

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Abstract

Neurons rely on the bloodstream for essential nutrients and oxygen, which is facilitated by an intricate coupling of the neuronal and vascular systems. Central to this neurovascular interaction is the vascular endothelial growth factor (VEGF) family, a group of secreted growth factors traditionally known for their roles in promoting endothelial cell proliferation, migration, and survival in the cardiovascular and lymphatic systems. However, emerging evidence shows that VEGFs also play indispensable roles in the nervous system, extending beyond their canonical angiogenic and lymphangiogenic functions. Over the past two decades, VEGFs have been found to exert direct effects on neurons, influencing key aspects of neuronal function independently of their actions on vascular cells. In particular, it has become increasingly evident that VEGFs also play crucial functions in the development, regulation, and maintenance of neuronal morphology. Understanding the roles of VEGFs in neuronal development is of high scientific and clinical interest because of the significance of precise neuronal morphology for neural connectivity and network function, as well as the association of morphological abnormalities with neurological and neurodegenerative disorders. This review begins with an overview of the VEGF family members, their structural characteristics, receptors, and established roles in vasculature. However, it then highlights and focuses on the exciting variety of neuronal functions of VEGFs, especially their crucial role in the development, regulation, and maintenance of neuronal morphology.

Introduction

The vascular endothelial growth factor (VEGF) family, part of the VEGF/ platelet-derived growth factor (PDGF) superfamily, consists of secreted glycoproteins. These proteins regulate endothelial cell proliferation, migration, and survival, playing essential roles in cardiovascular and lymphatic system development and maintenance [1]. In mammals, the VEGF family includes VEGFA—commonly known simply as VEGF-, placental growth factor (PlGF), VEGFB, VEGFC, and VEGFD [2,3,4,5,6,7,8]. VEGFD and VEGFC are classified as a subfamily within the VEGF family due to their close structural similarity [8, 9]. Additionally, VEGF-like proteins have been identified in Orf viruses (VEGFE) [10,11,12] and snake venom (VEGFF) [13,14,15]. A thorough phylogenetic analysis of the VEGF family is already available [16]. This review will focus on mammalian VEGFs.

Protein structure of the VEGF family

Alternative splicing, protein glycosylation, and proteolytic processing lead to a further diversity of VEGF isoforms with distinct biochemical properties and receptor interaction affinities [17,18,19,20]. Proteolytic processing serves as a critical mechanism in the VEGF family, particularly for VEGFC and VEGFD, regulating their maturation and receptor affinities [9, 19, 21]. Most VEGFs exist as monomers or anti-parallel homodimers and VEGFA, PIGF and VEGFB additionally form heterodimers [5, 21,22,23,24]. The VEGF homology domain (VHD) supports dimerization through a cystine knot motif, a characteristic of the VEGF/PDGF superfamily [25,26,27]. The cystine knot motif consists of eight or, in the case of VEGFD and VEGFC, nine regularly spaced cysteine residues which form intra- and intermolecular disulfide bonds that play a crucial role for structural stability and dimerization of VEGFs [8, 25,26,27,28]. However, the additional cysteine residue in VEGFC and VEGFD reduces dimer stability and homodimers of proteolytically processed mature VEGFD and VEGFC are predominantly non-covalently bound [9, 21, 28, 29].