New version page

Signaling Vascular Morphogenesis

This preview shows page 1-2 out of 6 pages.

View Full Document
View Full Document

End of preview. Want to read all 6 pages?

Upload your study docs or become a GradeBuddy member to access this document.

View Full Document
Unformatted text preview:

Signaling Vascular Morphogenesis and Maintenance Douglas Hanahan Science 277: 48-50, in Perspectives (1997)Blood vessels are constructed by two processes: vasculogenesis, whereby a primitive vascularnetwork is established during embryogenesis from multipotential mesenchymal progenitors, andangiogenesis, in which preexisting vessels (both in embryo and adult) send out capillary sprouts toproduce new vessels (1-3). Endothelial cells are centrally involved in each process: They migrateand proliferate and then assemble into tubes with tight cell-cell connections to contain the blood.Peri-endothelial support cells are recruited to encase the endothelial tubes, providing maintenanceand modulatory functions to the vessels; such cells include pericytes for small capillaries, smoothmuscle cells for larger vessels, and myocardial cells in the heart.The establishment and remodeling of blood vessels is controlled by paracrine signals, many ofwhich are protein ligands that bind and modulate the activity of transmembrane receptor tyrosinekinases (RTKs). This realization has emerged from the discovery and analysis of RTKs expressedon endothelial cells and of their ligands. Our basic view of RTK signaling has come from studies(performed largely in fibroblasts) of ligand-dependent autophosphorylation and activation of thebranched Ras pathways. The results suggest that most RTKs are similarly coupled into theintracellular signal transduction cascade and are capable of inducing cell proliferation. However, thelessons from endothelial cells present a far more complicated picture. This complexity ishighlighted by an article in this issue (4 page 55) of a ligand, called angiopoietin-2 (Ang2), thatinterferes with the kinase activity of an endothelial cell-selective RTK named Tie2. Remarkably,this inhibition of Tie2 kinase activity does not block endothelial cell proliferation and angiogenesis,but rather facilitates it.Tie2 has two ligands, Ang1 and Ang2. Another major regulator of vasculogenesis and angiogenesisis vascular endothelial growth factor (VEGF, also called vascular permeability factor, VPF). VEGFsignaling is itself mediated by two other endothelial cell-selective RTKs, called VEGF-R1 andVEGF-R2 (Flt1 and Flk1/KDR, respectively).Mice carrying homozygous disruptions in the two highly homologous VEGF receptors die in mid-gestation of acute vascular defects, implicating each in vasculogenesis and developmentalangiogenesis. However, the phenotypes are distinct--and instructive (see figure 1). VEGF-R2knockout mice, which die by embryonic day 8.5 (E8.5), lack both endothelial cells and a developinghematopoietic system, implicating VEGF as a signal in the determination first of a hemato-angioblast progenitor and then of endothelial cells (5). In contrast, VEGF-R1 knockout mice, whichalso die around E8.5, have normal hematopoietic progenitors and abundant endothelial cells, whichmigrate and proliferate but do not assemble into tubes and functional vessels (6). Thus, these highlyhomologous RTKs send distinctive signals in endothelial cells.Tie2 knockout mice die somewhat later in embryogenesis (E9.5 to E10.5). The Tie2 null phenotypeis distinct from that of the VEGF receptor knockouts and is also informative. Endothelial cells arepresent in normal numbers and are assembled into tubes, but the vessels are immature, lackingbranching networks and proper organization into large and small vessels (7, 8). There is also anabsence of the angiogenesis that vascularizes the neuroectoderm by capillary sprouting from theprimitive vascular network (or plexus). Notably, the vessels that do form lack an intimateencapsulation by peri-endothelial support cells. In the heart, the endocardium and myocardium donot show tight association and structural complexity; rather, the endocardial cells have aberrant,rounded shapes, are only loosely attached to the surrounding basement membrane, and in manylocations are disconnected from myocardial cells. Similar defects in vessel architecture are evidentin other tissues. Thus, the Tie2 tyrosine kinase appears to control the capability of endothelial cellsto recruit stromal cells to encase the endothelial tubes so as to stabilize the structure and modulatethe function of blood vessels.The fourth endothelial cell-selective RTK, Tie1, is remarkably similar in structure to Tie2 andappears to control another aspect of vessel integrity. Knockout mice lacking Tie1 die over a variableperiod, ranging from E14.5 to birth, of edema and hemorrhage, implicating the Tie1 signal incontrol of fluid exchange across capillaries and in hemodynamic stress resistance (8, 9).New insights into the surprising concept that the Tie2 RTK is primarily coupled into a signaltransduction circuit that elicits vessel maturation and maintains vessel integrity comes fromfunctional analyses of the angiopoietins that bind to Tie2 and modulate its activity (4, 10, 11). TheTie2 ligands Ang1 and Ang2 are both ~75-kD secreted proteins with considerable sequencehomology; each contains a coiled-coil and a fibrinogen-like domain. Both bind to the Tie2 receptorwith similar affinity, and neither binds to the related receptor Tie1. Yet their effects on Tie2 aredistinctive, as are their expression patterns in the mouse. Ang1 induces autophosphorylation of Tie2in cultured endothelial cells. In marked contrast, Ang2, which binds with similar affinity, does notinduce receptor phosphorylation. Rather, it can competitively inhibit Ang1--induced kinaseactivation of the Tie2 receptor. Thus Ang2 presents a negative signal to Tie2, a remarkableobservation given its high homology to Ang1.Moreover, this distinctive effect is apparently endothelial cell-specific. If a modified Tie2 is forciblyexpressed in 3T3 fibroblasts, both Ang1 and Ang2 induce receptor phosphorylation and yet do notstimulate fibroblast proliferation. Similarly, Ang1-induced autophosphorylation of Tie2 does notaffect endothelial cell growth in culture, consistent with the Tie2 knockout phenotype, whichindicated that Tie2 is not required for endothelial cell proliferation during vasculogenesis.Functional studies in transgenic and gene-knockout mice support the notion that Ang1 signals Tie2to recruit support cells, and that Ang2


Loading Unlocking...
Login

Join to view Signaling Vascular Morphogenesis and access 3M+ class-specific study document.

or
We will never post anything without your permission.
Don't have an account?
Sign Up

Join to view Signaling Vascular Morphogenesis and access 3M+ class-specific study document.

or

By creating an account you agree to our Privacy Policy and Terms Of Use

Already a member?