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The Role of Vascular Development in the Pathogenesis of Necrotizing Enterocolitis
Published in David J. Hackam, Necrotizing Enterocolitis, 2021
Isabelle G. De Plaen, Elizabeth Managlia, Xiaocai Yan
To exert its pro-angiogenic activity, VEGF-A binds to its primary receptor VEGFR2 present on endothelial cells (35). However, VEGF-A bioavailability is limited by its binding to VEGFR1, which has high affinity for VEGF-A, but only leads to weak tyrosine activity. Both VEGFR1 and VEGFR2 are needed for angiogenesis and normal development. In mice during the last few days of gestation (gestation of ±20 days), intestinal VEGF and VEGFR2 are highly expressed, but their expression markedly decreases after birth (11). The high level of VEGF/VEGFR2 in the intestine at the end of gestation suggests its requirement for the normal development of the fetal intestinal microvasculature.
Biological basis of angiogenesis and role of vascular endothelial growth factor-D
Published in A. R. Genazzani, Hormone Replacement Therapy and Cancer, 2020
The members of this family recognize three conserved endothelial cell-specific receptors which belong to the broad class of tyrosine kinase receptors. Different family members of the VEGF family recognize the three receptors differently. Some factors like P1GF and VEGF-B recognize only receptor VEGFR-1, while VEGF recognizes both VEGFR-1 and VEGFR-2. Finally, VEGF-C and
Tyrosine Kinase Inhibitors: Targets Other Than FLT3, BCR-ABL, and c-KIT
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
Suzanne R. Hayman, Judith E. Karp
The VEGF family members bind with different affinities to three receptor TKs belonging to the “7-Ig” or FLT gene family, FLT-1 [VEGF receptor (VEGFR)-1], KDR/Flk-1 (VEGFR-2), and FLT-4 (VEGFR-3), each of which contains seven extracellular immunoglobulin-like domains, one membrane-spanning segment, and a consensus TK sequence domain interrupted by a kinase-insert domain (54). The receptors are expressed primarily on vascular ECs with many of their actions mediated through PI3-kinase and activation of EC-derived NOS, and by bone marrow-derived cells as well (54). VEGF-A activity primarily is mediated through VEGFR-1 and VEGFR-2. Both VEGFRs are expressed in all adult vascular ECs, with the exception of the brain (58). VEGR-1 is also expressed on HSCs, leukemic blasts, vascular smooth muscle cells, and monocytes. An alternatively spliced soluble form of VEGFR-1 (s-FLT-1) is an inhibitor of VEGF. The functions of VEGFR-1 have not been characterized fully, and they appear to vary depending on cell type and maturational stage (55). VEGFR-2 activates vascular EC differentiation, proliferation, and migration and also induces vascular permeability (55). Most studies have found that VEGFR-1 is more commonly expressed in hematological malignancies than VEGFR-2 (55). VEGFR-1, not VEGFR-2, is associated with inhibition of HSC cycling, differentiation, and hematopoietic recovery in adults (55).
An appraisal of vascular endothelial growth factor (VEGF): the dynamic molecule of wound healing and its current clinical applications
Published in Growth Factors, 2022
Aakansha Giri Goswami, Somprakas Basu, Farhanul Huda, Jayanti Pant, Amrita Ghosh Kar, Tuhina Banerjee, Vijay Kumar Shukla
VEGFR-1, 2, and 3 are transmembrane proteins with tyrosine kinase activity (Olofsson et al. 1998). The exact mechanism of VEGF-induced intracellular activity is still a subject of intense study. Broadly, it appears that VEGF binding with the extracellular domains causes autophosphorylation of the receptor. This leads to activation of phospholipase Cγ, which activates protein kinase C and catalyzes the conversion of phosphatidylinositol 4,5-biphosphate (PIP2) to inositol 1,4,5-triphosphate (IP3) and diacylglycerol (Shibuya 2001). Finally, MAP-kinase (mitogen-activated protein kinase) activation leads to gene expression (Waltenberger et al. 1994). Although VEGFR-1 has the highest affinity for VEGF, its activation has very weak transcription effects, which puts a question mark on its true role in stimulating angiogenesis. On the other hand, VEGFR-2 is expressed significantly more than its counterpart and demonstrates 10 times more tyrosine kinase activity, which makes VEGFR-2 as the main mediator of VEGF function and a probable target for pharmacological intervention (Waltenberger et al. 1994). On the other hand, binding to its soluble receptors does not induce gene transcription and limits VEGF activity. It appears that VEGFR-1 and sVEGFR-1, 2 control VEGF overexpression and help in maintaining an angiogenic homeostasis.
Evaluation of the Effects of Intravitreal Aflibercept and Ranibizumab on Systemic Inflammatory and Cardiovascular Biomarkers in Patients with Neovascular Age-related Macular Degeneration
Published in Current Eye Research, 2021
The role of vascular endothelial growth factor (VEGF) in the pathogenesis of nAMD is obvious. VEGF is an important agent for a sound endothelium, also, prevents apoptosis, induces the expression of anti-apoptotic proteins, acts as a blood pressure regulator, and preserves the microvascular structure in many organ systems.2 The VEGF -VEGF receptor (R) interaction plays important role in angiogenesis and lymphangiogenesis. VEGFR2 has strong tyrosine kinase activity and is the main receptor that mediates the angiogenic process. VEGFR1 is expressed on the membrane of macrophages and monocytes and transmits important signals for the migration of these cells and the production of some cytokines/chemokines. The VEGFR1-macrophage axis mediates important inflammatory processes (arthritis, atherosclerosis) as well as promotes various diseases such as and tumor growth, metastasis, and lymphangiogenesis through proangiogenesis.3 Also, VEGF1-induced inflammation is accompanied by endothelial dysfunction (ED).4 ED is associated with serum concentrations of many factors involved in cardiovascular damage, such as C-reactive protein (CRP), low-density lipoprotein cholesterol (LDL-c), uric acid (UA), and hematological indices.5–8
Abicipar pegol for neovascular age-related macular degeneration
Published in Expert Opinion on Biological Therapy, 2020
Rehan M. Hussain, Christina Y. Weng, Charles C. Wykoff, Raya A. Gandhi, Seenu M. Hariprasad
The aberrant vascular growth and exudation in nAMD are driven by upregulation of cytokines involved in angiogenesis, primarily vascular endothelial growth factor-A (VEGF) [6]. This cytokine is also one of the most potent inducers of permeability and was, in fact, originally called vascular permeability factor [7,8]. The VEGF family of proteins include VEGF-A, VEGF-B, VEGF-C, VEGF-D and VEGF-E, and placental growth factor (PLGF) [9]. The actions of VEGF family members are mediated by the activation of transmembrane tyrosine kinase receptors. There are various isoforms of VEGF resulting from alternative mRNA splicing of exons, which determine its heparin-binding ability and diffusion through tissues [9]. VEGF binds to VEGF receptors (VEGFR1 and VEGFR2), and mediates angiogenesis by promoting endothelial cell migration, proliferation, and survival [10]. VEGF also possesses inflammatory properties through its capacity to mediate microvascular permeability and increase adhesion of leukocytes [11].