Effects of vascular endothelial growth factors and their receptors on megakaryocytes and platelets and related diseases

Abstract

It is well known that vascular endothelial growth factors (VEGFs) and their receptors (vascular endothelial growth factor receptors, VEGFRs) are expressed in different tissues, and VEGF-VEGFR loops regulate a wide range of responses, including metabolic homeostasis, cell proliferation, migration and tubuleogenesis. As ligands, VEGFs act on three structurally related VEGFRs (VEGFR1, VEGFR2 and VEGFR3 [also termed FLT1, KDR and FLT4, respectively]) that deliver downstream signals. Haematopoietic stem cells (HSCs), megakaryocytic cell lines, cultured megakaryocytes (MKs), primary MKs and abnormal MKs express and secrete VEGFs. During the development from HSCs to MKs, VEGFR1, VEGFR2 and VEGFR3 are expressed at different developmental stages, respectively, and re-expressed, e.g., VEGFR2, and play different roles in commitment, differentiation, proliferation, survival and polyplodization of HSCs/MKs via autocrine, paracrine and/or even intracrine loops. Moreover, VEGFs and their receptors are abnormally expressed in MK-related diseases, including myeloproliferative neoplasms, myelodysplastic syndromes and acute megakaryocytic leukaemia (a rare subtype of acute myeloid leukaemia), and they lead to the disordered proliferation/differentiation of bone marrow cells and angiogenesis, indicating that they are closely related to these diseases. Thus, targeting VEGF-VEGFR loops may be of potential therapeutic value.

Tumor Angiogenesis and Anti-Angiogenic Strategies for Cancer Treatment

“…By binding to specific soluble, membrane-bound vascular endothelial growth factor receptors (VEGFR) or co-receptors, they modulate a series of responses, such as cell proliferation and migration, metabolic homeostasis, and tubulogenesis. Moreover, VEGFs rigorously control the physiological vasculogenesis and angiogenesis, the blood and lymphatic function in healthy or diseased adult tissues [30][31][32], and vascular permeability [33].…”

“…The VEGF family comprises a series of structurally and functionally related proteins, namely VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, and placental growth factor (PlGF) [30,32,34]. VEGF-A is the most studied member of the VEGF superfamily, as it is the key angiogenesis regulator and the most potent inducer of angiogenesis [31,34].…”

“…VEGF-A is the most studied member of the VEGF superfamily, as it is the key angiogenesis regulator and the most potent inducer of angiogenesis [31,34]. VEGF-A is selectively spliced to produce seven proangiogenic and five anti-angiogenic isoforms, e.g., VEGF-A 121 , VEGF-A 145 , VEGF-A 165 , VEGF-A 189 , and VEGF-A 206 (indicating the number of amino acid residues in each polypeptide) [30][31][32]. VEGF-B is abundantly found in the cardiac and skeletal muscle, contributing to the pulmonary vascular remodeling after exposure to chronic hypoxia, VEGF-C and VEGF-D are key lymphangiogenesis regulators, and VEGF-E is an Orf virus-encoded VEGF homolog, which is not present in the human genome [34][35][36][37].…”

“…VEGFs exhibit their function by binding to three structurally related VEGFRs, namely VEGFR1 (FLT1), VEGFR2 (KDR, FLK1), and VEGFR3 (FLT4), which comprise three domains: an extracellular ligand-binding region with an Ig-like domain, a transmembrane domain, and a tyrosine kinase domain within the intracellular domain. VEGF binding to VEGFRs promotes the tyrosine kinase enzyme activation in the intracellular receptor domain and subsequently leads to the phosphorylation of the tyrosine residues, thus activating specific intracellular signaling pathways [30,32,38]. VEGFR1 is expressed in monocytes, macrophages, hematopoietic stem cells, vascular smooth cells, and leukemic cells, VEGFR2, in vascular endothelial cells, endothelial progenitor cells, and megakaryocytes, and VEGF3, in lymphoid endothelial cells [30,38,39].…”

“…VEGF binding to VEGFRs promotes the tyrosine kinase enzyme activation in the intracellular receptor domain and subsequently leads to the phosphorylation of the tyrosine residues, thus activating specific intracellular signaling pathways [30,32,38]. VEGFR1 is expressed in monocytes, macrophages, hematopoietic stem cells, vascular smooth cells, and leukemic cells, VEGFR2, in vascular endothelial cells, endothelial progenitor cells, and megakaryocytes, and VEGF3, in lymphoid endothelial cells [30,38,39]. VEGFs can also interact with other proteins, including neuropilins, integrins, cadherins, or heparan sulphate proteoglycans.…”