Research Report 2010 - MDC

Structure of the GroupFerdinand le NobleGroup LeaderProf. Dr. Ferdinand le NobleScientistsDr. rer. Nat. Christian KleinDr. rer. Nat. Yu ShiDr. rer. Nat. Philipp HillmeisterDr. vet. Med. Andrei DuelsnerGraduate StudentsJanna KruegerDong LiuAnna Maria RohdeTechnical AssistantsJanine MikuttaKatja ScholzAnja ZimmerSecretariatBrunhilde PoppeAngiogenesis and CardiovascularPathologyVascular network remodeling and the formation of new blood vessels (angiogenesis andarteriogenesis) plays an important role in the pathophysiology of ischemic cardiovasculardisease, hypertension, and cancer, which are the most common causes of mortality in westernsociety. Our goal is to generate novel genetic insights in the regulation of vascular developmentthat can translate into therapeutic strategies. Our research projects aim at understanding themolecular regulation of angiogenesis and arteriogenesis. We focus on three crucial aspects:differentiation and guidance of angiogenic vessel sprouts by endothelial tip cells, imprinting ofarterial-venous identity in blood vessels by neural guidance genes and hemodynamic factors,and the formation and adaptation of native collaterals in the context of ischemic diseases.Using an integrative molecular and physiological approach in zebrafish, xenopus, and mouse,we want to investigate in which way manipulation of guidance molecules can betherapeutically relevant.Tip Cell biology and Vessel GuidanceRecent studies of vascular network development in theembryo identified several novel aspects of angiogenesiscrucial to generate a functional and stable branchedvascular network. These aspects include: a) the specificationof arterial and venous identity in vessels, b) thedifferentiation and guidance of endothelial tip cells inangiogenic vessels, c) the formation of branches andnetwork patterning.We discovered that neural guidance genes expressed inthe vascular system control vessel branching morphogenesisby regulating the movement of endothelial tipcells at the leading edge of angiogenic vessel sprouts.We demonstrated that delta-like 4 Notch signaling controlsthe differentiation of endothelial cells into tip cellsin response to VEGF gradients. The recognition thatbranching morphogenesis is controlled by a single celltype, the tip cell, that can sense attractant and repulsivesignaling cues opens novel therapeutic avenues. Ourcurrent research endeavours therefore focus at elucidatingthe transcriptome and proteome of endothelialtip cell differentiation and function. We identified severalnovel candidate molecules involved in endothelial tipcell differentiation and vessel guidance events. We performedloss and gain of function experiments inzebrafish and mouse models to elucidate the mechanismof action of these molecules. Our candidatesappear to directly affect tip cell differentiation fromendothelial cells and coordination of their movement inthe extracellular matrix. Interestingly, the guidancefunction of several of these navigation molecules alsoappears to play a pivotal function in organogenesis ofheart, and liver. In this context we provided the proof ofconcept that in pathological conditions interferencewith guidance molecules maybe beneficial to preventthe development of dilated cardiomyopathy in hypoxichearts.20 Cardiovascular and Metabolic Disease Research