TIE1 AND TIE2 RECEPTOR TYROSINE KINASES INVERSELY REGULATE EMBRYONIC ANGIOGENESIS BY THE MECHANISM OF INTUSSUSCEPTIVE MICROVASCULAR GROWTH

As shown previously, TIE1 and TIE2 receptor tyrosine kinases are speci fically expressed in endothelial cells during embryonic angiogenesis. A detailed analysis of the vascular malformations of homozygous mice f or a targeting mutation of both receptors was performed at the histolo gical and cellular level. The data demonstrate that the TIE1 and TIE2 receptor inversely and concomitantly mediate interactions between endo thelial cells with their extracellular matrix and with surrounding mes enchymal cells. These interactions are obviously crucial for normal en dothelial cell motility and/or attachment and also for recruitment of periendothelial cells. The analysis of the TIE2-deficient embryos demo nstrates how these cell/cell- and cell/matrix interactions subsequentl y influence the formation of normally structured tissue folds that div ide the vessel lumen. They are also essential for the formation of ves sel loops that compose a new vascular network and for the development of the ventricle in the heart. Fold and loop formation follow the prin ciples of intussusceptive microvascular growth. The localization of th e cardiovascular malformations corresponds to the temporal and spatial expression pattern of the TIE2 receptor. Angiopoietin-1, a ligand tha t activates the TIE2 receptor, is expressed in mesenchymal cells surro unding the endothelium. This local relationship is indicative of a par acrine regulation. (C) 1998 Academic Press.