Vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) are uniquely required to balance the formation of new blood vessels with the maintenance and remodelling of existing ones, during development and in adult tissues. Recent advances have greatly expanded our understanding of the tight and multi-level regulation of VEGFR2 signalling, which is the primary focus of this Review. Important insights have been gained into the regulatory roles of VEGFR-interacting proteins (such as neuropilins, proteoglycans, integrins and protein tyrosine phosphatases); the dynamics of VEGFR2 endocytosis, trafficking and signalling; and the crosstalk between VEGF-induced signalling and other endothelial signalling cascades. A clear understanding of this multifaceted signalling web is key to successful therapeutic suppression or stimulation of vascular growth.

Mechanisms and regulation of endothelial VEGF receptor signalling

Ageing is a major risk factor for many neurological pathologies, but its mechanisms remain unclear. Unlike other tissues, the parenchyma of the central nervous system (CNS) lacks lymphatic vasculature and waste products are removed partly through a paravascular route. (Re)discovery and characterization of meningeal lymphatic vessels has prompted an assessment of their role in waste clearance from the CNS. Here we show that meningeal lymphatic vessels drain macromolecules from the CNS (cerebrospinal and interstitial fluids) into the cervical lymph nodes in mice. Impairment of meningeal lymphatic function slows paravascular influx of macromolecules into the brain and efflux of macromolecules from the interstitial fluid, and induces cognitive impairment in mice. Treatment of aged mice with vascular endothelial growth factor C enhances meningeal lymphatic drainage of macromolecules from the cerebrospinal fluid, improving brain perfusion and learning and memory performance. Disruption of meningeal lymphatic vessels in transgenic mouse models of Alzheimer’s disease promotes amyloid-β deposition in the meninges, which resembles human meningeal pathology, and aggravates parenchymal amyloid-β accumulation. Meningeal lymphatic dysfunction may be an aggravating factor in Alzheimer’s disease pathology and in age-associated cognitive decline. Thus, augmentation of meningeal lymphatic function might be a promising therapeutic target for preventing or delaying age-associated neurological diseases.

/pdf/functional-aspects-of-meningeal-lymphatics-in-ageing-and-2zv11ccfip.pdf

Functional aspects of meningeal lymphatics in ageing and Alzheimer’s disease

Vascular endothelial growth factor (VEGF) represents a growth factor with important pro-angiogenic activity, having a mitogenic and an anti-apoptotic effect on endothelial cells, increasing the vascular permeability, promoting cell migration, etc. Due to these effects, it actively contributes in regulating the normal and pathological angiogenic processes. In humans, the VEGF family is composed of several members: VEGF-A (which has different isoforms), VEGF-B, VEGF-C, VEGF-D, VEGF-E (viral VEGF), VEGF-F (snake venom VEGF), placenta growth factor (PlGF), and, recently, to this family has been added endocrine gland-derived vascular endothelial growth factor (EG-VEGF). VEGF binds to tyrosine kinase cell receptors (VEGFRs): VEGFR-1 [Fms-like tyrosine kinase 1 (Flt-1)], VEGFR-2 [kinase insert domain receptor (KDR) in human; fetal liver kinase 1 (Flk-1) in mouse] and VEGFR-3 [Fms-like tyrosine kinase 4 (Flt-4)]. While VEGFR-1 and VEGFR-2 are expressed predominantly on vascular endothelial cells, VEGFR-3 is expressed especially on lymphatic endothelial cells. VEGFR-2 has the strongest pro-angiogenic activity and a higher tyrosine kinase activity than VEGFR-1. Endothelial cells also express co-receptors, such as neuropilin-1 (NP-1) and neuropilin-2 (NP-2), which modulate tyrosine kinase receptor activity. Both VEGF and VEGFRs are expressed not only on endothelial cells, but also on non-endothelial cells. This article aims to highlight the most recent data referring to the VEGF family and its receptors, as well as its implications in the angiogenesis process. At present, blocking angiogenesis in cancer or in other pathological processes, using anti-VEGF and anti-VEGFRs therapies, is considered to be extremely important.

Vascular endothelial growth factor (VEGF) - key factor in normal and pathological angiogenesis.

Endothelial cells that line capillaries are not just passive conduits for delivering blood. Tissue-specific endothelium establishes specialized vascular niches that deploy sets of growth factors, known as angiocrine factors. These cues participate actively in the induction, specification, patterning and guidance of organ regeneration, as well as in the maintainance of homeostasis and metabolism. When upregulated following injury, they orchestrate self-renewal and differentiation of tissue-specific resident stem and progenitor cells into functional organs. Uncovering the mechanisms by which organotypic endothelium distributes physiological levels of angiocrine factors both spatially and temporally will lay the foundation for clinical trials that promote organ repair without scarring.

Angiocrine functions of organ-specific endothelial cells

Adult Mammalian Neural Stem Cells and Neurogenesis: Five Decades Later

Vascular endothelial growth factor receptor 3 controls neural stem cell activation in mice and humans.

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Vascular endothelial growth factor receptor 3 controls neural stem cell activation in mice and humans.