Receptor Tyrosine Kinase-Mediated Angiogenesis

Abstract

The endothelial cell is the essential cell type forming the inner layer of the vasculature. Two families of receptor tyrosine kinases (RTKs) are almost completely endothelial cell specific: the vascular endothelial growth factor (VEGF) receptors (VEGFR1-3) and the Tie receptors (Tie1 and Tie2). Both are key players governing the generation of blood and lymphatic vessels during embryonic development. Because the growth of new blood and lymphatic vessels (or the lack thereof ) is a central element in many diseases, the VEGF and the Tie receptors provide attractive therapeutic targets in various diseases. Indeed, several drugs directed to these RTK signaling pathways are already on the market, whereas many are in clinical trials. Here we review the VEGFR and Tie families, their involvement in developmental and pathological angiogenesis, and the different possibilities for targeting them to either block or enhance angiogenesis and lymphangiogenesis. ANGIOGENESIS IN DEVELOPMENT Basics of Vasculature

Tie1 controls angiopoietin function in vascular remodeling and inflammation

“…While angiogenesis research has focused primarily on the mechanisms of vessel sprouting, the remodeling of vascular networks in adult organs has received less attention. Vascular integrity and remodeling are governed by the cooperative interaction of endothelial growth factors and inflammatory cytokines (3).…”

TIMAP promotes angiogenesis by suppressing PTEN-mediated Akt inhibition in human glomerular endothelial cells

“…Angiogenesis involves the sprouting and elongation of new blood vessels from preexisting vessels followed by stabilization and vessel specification (28). This process is crucial for normal blood vessel formation and patterning during embryonic development, for postembryonic blood vessel repair (5), and remodeling in response to hypoxia, in the female reproductive cycle, and for the establishment of the placental vasculature.…”

“…While endothelial cells (EC) at the tip of the angiogenic sprout determine the direction and pattern of new blood vessel growth, elongation of the new vessel stalk requires EC proliferation (13). A complex array of growth factors and their intracellular signaling systems regulate angiogenesis, including vascular endothelial growth factors (VEGFs), fibroblast growth factors (FGFs), the angiopoietins, and the transforming growth factor-␤ (TGF-␤) family (28).…”

The Antiparasitic Drug, Potassium Antimony Tartrate, Inhibits Tumor Angiogenesis and Tumor Growth in Nonsmall-Cell Lung Cancer

“…In fact, no identical pattern of angiogenesis has been found in tumors, indicating that angiogenesis is comprehensively triggered and mediated by different pathways (Lund et al, 1998). Several regulatory and signaling molecules controlling angiogenesis have been characterized, including potent growth factors, such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and angiopoietin (Ferrara and Kerbel, 2005;Presta et al, 2005;Saharinen et al, 2011), receptor tyrosine kinases (RTKs) (Jeltsch et al, 2013), and molecules involved in signaling cascades, such as Src kinase, focal adhesion kinase (FAK), extracellular signal-regulated kinase (ERK), and AKT (Downward, 2003;McLean et al, 2005;Kim et al, 2009;Liu et al, 2009;Lemmon and Schlessinger, 2010). These molecules have been exploited for their potential as drug targets for antiangiogenic therapy.…”