Wide implications of VEGF, from physiological circumstances to pathological conditions

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VEGF family members, receptors and mode of action

There are five VEGF variants including VEGF-A, VEGF-B, VEGF-C, VEGF-D, placental growth factor; all described in mammals, as well as VEGF-E (found in Parapoxviridae), VEGF-F (also called svVEG-F for snake venom VEGF found in viper venom), each with structurally similar proteins involved in the regulation and differentiation of the vascular system, particularly in the blood and lymph vessels (90;97;101;102). Table 4 shows the similarities and differences of the human VEGF members’ family.
Among these subtypes, VEGF-A has a main role in mediating angiogenic effects (90;101). VEGF-A binds to and activates two corresponding receptors on the cell membrane of endothelial cells, namely VEGF receptor 1(also VEGFR-1 of Flt-1) and VEGF receptor-2(also VEGFR-2 or FlK-1 or KDR). These receptors regulate physiologic and pathologic angiogenesis (90). VEGFR-2 is mainly associated with pathological angiogenesis, such as vascular network formation in tumors and diabetic retinopathy. VEGFR-1, however, has a dual role; in embryo it has a negative effect on angiogenesis via isolation of VEGF-A, while in adults it has a main influence on monocytes and endothelial cells that stimulate angiogenesis (90;93;101).

VEGFA gene, related isoforms and proteins

The human VEGF-A gene is organized in eight exons, separated by seven introns and is located in chromosome 6p21.3. The coding region spans approximately 14 kb. Alternative exon splicing results in the generation of four different isoforms, having 121, 165, 189, and 206 amino acids, respectively, after signal sequence cleavage (VEGF121, VEGF165, VEGF189, VEGF206). VEGF165, the predominant isoform, lacks the residues encoded by exon 6, whereas VEGF121 lacks the residues encoded by exons 6 and 7. Less frequent splice variants have been also reported, including VEGF145, VEGF183, as well as VEGF121b, VEGF145b,VEGF165b, VEGF189b the variants reported to have paradoxically an inhibitory effect on VEGF induced mitogenesis (90). Figure 4 shows more details of VEGF gene, its isoforms and protein.
Solution of the crystal structure of VEGF has shown that VEGF forms an antiparallel homodimer covalently linked by two disulfide bridges (90;104)(Figure 5). This mode of dimerization is similar to that of the PDGF monomers. VEGF121 is an acidic polypeptide that fails to bind to heparin. VEGF189 and VEGF206 are highly basic and bind to heparin with high affinity. VEGF121 is a freely diffusible protein. In contrast, VEGF189 and VEGF206 are almost completely sequestered in the extracellular matrix. VEGF165 has intermediate properties, because it is secreted, but a significant fraction remains bound to the cell surface and extracellular matrix. Several researches suggest that VEGF165 has optimal characteristics of bioavailability and biological potency (90;101;104).

VEGF expressing cells and tissues

VEGF is secreted under normal conditions by endothelial cells, platelets and vascular smooth muscle cells, macrophages, monocytes, lung epithelial cells, kidney epithelial cells (podocytes), follicular cell in the pituitary, corpus luteum cells, adipose derived stem cells adipose stromal cells and in abnormal conditions by all mentioned cells and omentum adipocytes, retinal pigment epithelial cell, synovial cells and by several tumor cells in vivo and in vitro. Regulation of VEGF levels has been reported to occur at the gene transcriptional, translational, and posttranslation levels. Transcriptional regulation of VEGF expression has been studied extensively, because the effect of most genetic and epigenetic factors on VEGF expression is mediated by the regulation of the VEGF gene transcription. VEGF mRNA is expressed in several normal human tissues including lung, kidney, liver, gastric mucosa and at a lower level in breast tissue (108). Several evidences indicate that peripheral blood mononuclear cells, circulating and tissue macrophages (peritoneal macrophage), monocytes, fibroblasts cell line CCD 18, mast cells and adipocytes express the VEGF gene as well (108).

VEGF expression influencing factor

VEGF expression can be extremely enhanced by numerous microenvironmental factors such as hypoxia, acidosis, oxidative stress and disregulated production of several growth factors and cytokines such as insulin growth factor-1, hepatocyte growth factor, fibroblast growth factor, epidermal growth factor, vascular endothelial growth factor, platelet drivating growth factor (Table 6) (109). Many other stimuli can modulate VEGF expression including iron chelators, glucose deficiency, prostaglandins, serum starvation, ionizing radiation and ultraviolet B radiation. It should be mentioned that VEGF expression induced by these signals may result in a function not as an angiogeneic factor but rather as a surviving element for preexisting vessels and endothelial cells (109).

VEGF transcription factors

Each of these regulators acts through transcriptional factors. Many transcriptional factors are involved in the up regulation or repression of VEGF gene transcription (110), including: hypoxia inducible factors (HIF1 and HIF2), specific protein 1 (Sp1), activating protein-1 (Ap-1), nuclear factor kappa b (NF-κB) and some of other factors. The way that these factors come together to regulate the cell type-, tissue- and context-specific expression of each of the VEGF gene remains unclear (111).

VEGF functions in angiogenesis and lymphangiogenesis

A well-documented in vitro activity of VEGF is the ability to promote growth of vascular endothelial cells derived from arteries, veins, and lymphatics. VEGF promotes angiogenesis in tridimensional in vitro models, inducing confluent microvascular endothelial cells to invade collagen gels and form capillary-like structures. Also, VEGF induces sprouting from rat aortic rings embedded in a collagen gel. VEGF also elicits a pronounced angiogenic response in a variety of in vivo models including the chick chorioallantoic membrane, the rabbit cornea; the matrigel plug in mice, the primate iris, etc. (90;104). VEGF delivery also induces lymphangiogenesis in mice, at least in some circumstances. Ergun et al. (112) have proposed that induction of carcinoembryonic antigen-related cell adhesion 1, a membrane glycoprotein expressed in some microvascular endothelial cells, mediates some of the angiogenic effects of VEGF.
VEGF is also a survival factor for endothelial cells, both in vitro and in vivo (113;114). In vitro, VEGF prevents endothelial apoptosis induced by serum starvation. Such activity is mediated by the phosphatidylinositol 3-kinase (PI3 kinase)/Akt pathway (113;114).
Although endothelial cells are the primary targets of VEGF, several studies have reported mitogenic effects also on other cell types, such as retinal pigment epithelial cells (90;101;104), pancreatic duct cells, and Schwann cells. Compernolle and colleagues (115) have also shown that VEGF stimulates surfactant production by alveolar type II cells, resulting in a protective effect from respiratory distress syndrome in mice. Other studies have emphasized the potential role of VEGF as a neuronal protective factor, and a haplotype in the VEGF gene promoter associated with reduced VEGF expression has been reported to be is a risk factor for amyotrophic lateral sclerosis(104). VEGF also has several secondary influences through the induction of a number of active enzymes that have a wide range of actions, such as nitric oxide, plasminogen activators and endothelial cell decay-accelerating factor.


Influences of VEGF on bone marrow cells and hematopoiesis

The ability of monocyte chemotaxis promotion was the earliest evidence that VEGF can affect blood cells. After that, VEGF was reported to have hematopoietic effects, inducing colony formation by mature subsets of granulocyte-macrophage progenitor cells. Notably, VEGF infusion to adult mice inhibits dendritic cell development, leading to the hypothesis that VEGF facilitates tumor growth by allowing escape of tumors from the host immune system. Also, VEGF increased production of B cells and the generation of immature myeloid cells. Some studies suggest that VEGF controls hematopoietic stem cells survival during hematopoietic repopulation (116)

Increasing of vascular permeability and hemodynamic effects

Nowadays, VEGF is known also as vascular permeability factor, based on its ability to induce vascular leakage. The permeability-enhancing activity of this molecule underlies dominant roles in inflammation and other pathological conditions. In accordance with a role in the regulation of vascular permeability, VEGF induces endothelial fenestration in some vascular beds and in cultured adrenal endothelial cells (90;104). Different studies have shown a critical role of nitric oxide (NO) in VEGF-induced vascular permeability as well as angiogenesis. Fukumura et al.(117) have verified the relative contribution of the NO synthase (NOS) isoforms, inducible NOS and endothelial NOS (eNOS) to these processes.

Table of contents :

2.1. Cardiovascular diseases
2.1.1 Risk factors of cardiovascular disease Principal risk factors of cardiovascular disease Predisposing risk factors of cardiovascular disease Potential risk factors of cardiovascular disease
2.1.2. Pathophysiology of cardiovascular diseases
2.1.3 Systems biology and the network of gene-environment interactions of cardiovascular diseases
2.2. Metabolic syndrome
2.2.1. Metabolic syndrome historical mirror
2.2.2 Metabolic syndrome increases the risk of atherosclerosis and T2D
2.2.3. Metabolic syndrome risk factors
2.2.4. Proposed metabolic syndrome’s pathophysiologies Explanatory molecular pathways disturbance underlying of MetS
2.2.5. Endothelial dysfunction and metabolic syndrome
2.2.6. Inflammation role in the pathophysiology of metabolic syndrome
2.2.7. Genetic and ethnic variations in metabolic syndrome
2.2.8. Genetic heritability of metabolic syndrome related components
2.2.9. Diagnostic criteria of metabolic syndrome
2.2.10. Metabolic syndrome Epidemiology in the world
2.3. Vasculogenesis and angiogenesis
2.3.1. Vascular system in embryonic period Vasculogenesis steps and angiogenesis forms
2.3.2 Angiogenesis regulatory factors
2.3.3. Vascular endothelial growth factor (VEGF) VEGF brief history VEGF family members, related receptors and mode of action VEGFA gene, related isoforms and proteins VEGF heritability Regulation of VEGF expression VEGF producing and expressing cells and tissues VEGF expression influencing factors VEGF transcription factors VEGF activities VEGF functions in angiogenesis and lymphangiogenesis Influence of VEGF on bone marrow cells and hematopoiesis Increasing of vascular permeability and hemodynamic effects Clinical significance of VEGF Wide implications of VEGF, from physiological circumstances to pathological conditions Wound healing Diabetes and its related complications Hypertension Essential hypertension Pre-eclampsia (pregnancy-induced hypertension) Diabetic nephropathy Obesity and metabolic syndrome Atherosclerosis VEGF gene single nucleotide polymorphisms and associated diseases
3.1. Influences of pre-analytical variables on VEGF gene expression and circulating concentrations
3.2. Identification of cis- and trans-Acting Genetic Variants Explaining Up to Half the Variation in Circulating Vascular Endothelial Growth Factor Levels.
3.3. Associations of VEGF with adhesion and inflammation molecules in a healthy population
3.4. Associations of vascular endothelial growth factor cis and trans-acting genetic variants with metabolic syndrome and its related components
3.5. High Prevalence of Metabolic Syndrome in Iran in Comparison with France
F.2.1. Influence des variables pré-analytique sur l’expression génétique et les taux de VEGF circulant.
F.2.2. Identification de variants génétiques agissant en cis et trans expliquant jusqu’ à la moitié de la variation des taux circulants du facteur de croissance de l’endothélium vasculaire
F.2.3. Association du VEGF à des molécules d’adhésion et de l’inflammation dans une population saine.
F.2.4. Association des variants génétiques du VEGF agissant en cis et en trans avec le syndrome métabolique et ses composants
F.2.5. Prévalence élevée du syndrome métabolique en Iran en comparaison avec la France


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