VDR (vitamin D(1,25- dihydroxyvitamin D3)receptor), also known as NR1I1, belongs to the NR1I family, NR1 subfamily. It is composed of three domains: a modulating N-terminal domain, a DNA-binding domain and a C-terminal ligand-binding domain. Vitamin D receptors (VDRs) are members of the NR1I family, which also includes pregnane X (PXR) and constitutive androstane (CAR) receptors, that form heterodimers with members of the retinoid X receptor family. VDRs repress expression of 1alpha-hydroxylase (the proximal activator of 1,25(OH)2D3) and induce expression of the 1,25(OH)2D3 inactivating enzyme CYP24. Also, it has recently been identified as an additional bile acid receptor alongside FXR and may function to protect gut against the toxic and carcinogenic effects of these endobiotics. VDR is expressed in the intestine, thyroid and kidney and has a vital role in calcium homeostasis. It is the nuclear hormone receptor, also called transcription factor that mediates the action of vitamin D3. Inherited mutations in the VDR gene leads to rickets.
Cadherins (Calcium dependent adhesion molecules) are a class of transmembrane proteins. Cadherin-5, also known as VE-cadherin, CDH5 and CD144, an endothelial specific cell-cell adhesion molecule, plays a pivotal role in the formation, maturation and remodeling of the vascular wall. VE-Cadherin is widely considered to be specific for vascular endothelia in which it is either the sole or the predominant cadherin, often co-existing with N-cadherin. This specificity of VE-cadherin for vascular endothelial cells is important not only in blood and lymph vessel biology and medicine, but also for cell-type-based diagnoses, notably those of metastatic tumors. As a classical cadherin, VE-Cadherin links endothelial cells together by homophilic interactions mediated by its extracellular part and associates intracellularly with the actin cytoskeleton via catenins. Mechanisms that regulate VE-cadherin-mediated adhesion are important for the control of vascular permeability and leukocyte extravasation. In addition to its adhesive functions, VE-Cadherin regulates various cellular processes such as cell proliferation and apoptosis and modulates vascular endothelial growth factor receptor functions. Consequently, VE-cadherin is essential during embryonic angiogenesis.
Human VEGF121; also known as Vascular endothelial growth factor A; VEGFA; Vascular permeability factor; VPF and VEGF; is a homodimeric; heparin-binding glycoprotein which belongs to the platelet-derived growth factor (PDGF)/vascular endothelial growth factor (VEGF) family. VEGF-A is a glycosylated mitogen that specifically acts on endothelial cells and has various effects; including mediating increased vascular permeability; inducing angiogenesis; vasculogenesis; permeabilization of blood vessels and endothelial cell growth; increasing microvascular permeability; promoting cell migration and inhibiting apoptosis. Alternatively spliced transcript variants of VEGF-A encod either secreted or cell-associated isoforms. The lymphangiogenesis may be promoted by upregulation of VEGF121; which may in turn act in part via induction of VEGF-C. It binds to the FLT1/VEGFR1 and KDR/VEGFR2 receptors; heparan sulfate and heparin. NRP1/Neuropilin-1 binds isoforms VEGF-165 and VEGF-145. Isoform VEGF165B binds to KDR but does not activate downstream signaling pathways; does not activate angiogenesis and inhibits tumor growth.
Vascular endothelial growth factor (VEGF); also known as vascular permeability factor (VPF) and VEGF-A; is a potent mediator of both angiogenesis and vasculogenesis in the fetus and adult. It is a member of the platelet-derived growth factor (PDGF)/vascular endothelial growth factor (VEGF) family and often exists as a disulfide-linked homodimer. VEGF-A protein is a glycosylated mitogen that specifically acts on endothelial cells and has various effects; including mediating increased vascular permeability; inducing angiogenesis; vasculogenesis and endothelial cell growth; promoting cell migration; inhibiting apoptosis and tumor growth. VEGF-A protein is also a vasodilator that increases microvascular permeability; thus it was originally referred to as vascular permeability factor.
Mouse Vascular endothelial growth factor (VEGF or VEGF-A), is a potent mediator of both angiogenesis and vasculogenesis in the fetus and adult. It is a member of the PDGF/VEGF growth factor family that is characterized by a cystine knot structure formed by eight conserved cysteine residues. Alternately spliced isoforms of 120, 164 and 188 aa found in mouse. VEGF binds the type I transmembrane receptor tyrosine kinases VEGF R1 (also called Flt-1) and VEGF R2 (Flk-/KDR) on endothelial cells.Although affinity is highest for binding to VEGF R1, VEGF R2 appears to be the primary mediator of VEGF angiogenic activity. VEGF is required during embryogenesis to regulate the proliferation, migration, and survival of endothelial cells.It may play a role in increasing vascular permeability during lactation, when increased transport of molecules from the blood is required for efficient milk protein synthesis.
Mouse vascular endothelial growth factor D, (VEGFD) is a member of the platelet-derived growth factor/vascular endothelial growth factor (PDGF/VEGF) family. VEGFD is a secreted protein and highly expressed in fetal and adult lung. It undergoes a complex proteolytic maturation, generating multiple processed forms that bind and activate VEGFR-2 and VEGFR-3 receptors. The structure and function of this protein is similar to VEGFC. VEGFD is growth factor which active in angiogenesis, lymphangiogenesis, and endothelial cell growth, stimulating their proliferation and migration and also has effects on the permeability of blood vessels.
VEGFR2, also called as KDR or Flk-1, is identified as the receptor for VEGF and VEGFC and an early marker for endothelial cell progenitors, whose expression is restricted to endothelial cells in vivo. VEGFR2 was shown to be the primary signal transducer for angiogenesis and the development of pathological conditions such as cancer and diabetic retinopathy. It has been shown that VEGFR2 is expressed mainly in the endothelial cells, and the expression is upregulated in the tumor vasculature. Thus the inhibition of VEGFR2 activity and its downstream signaling are important targets for the treatment of diseases involving angiogenesis. VEGFR2 transduces the major signals for angiogenesis via its strong tyrosine kinase activity. However, unlike other representative tyrosine kinase receptors, VEGFR2 does not use the Ras pathway as a major downstream signaling but rather uses the phospholipase C-protein kinase C pathway to signal mitogen-activated protein (MAP)-kinase activation and DNA synthesis. VEGFR2 is a direct and major signal transducer for pathological angiogenesis, including cancer and diabetic retinopathy, in cooperation with many other signaling partners; thus, VEGFR2 and its downstream signaling appear to be critical targets for the suppression of these diseases. VEGF and VEGFR2-mediated survival signaling is critical to endothelial cell survival, maintenance of the vasculature and alveolar structure and regeneration of lung tissue. Reduced VEGF and VEGFR2 expression in emphysematous lungs has been linked to increased endothelial cell death and vascular regression.
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