Our group aims to find novel genetic insights in the regulation of cardiac and vascular development in the embryo that can translate into therapeutic strategies useful for targeting hypertension, heart failure, cardiac ischemia, and cancer in humans.
Keywords:
developmental biology, angiogenesis, arteriogenesis, neural genes, cardiac morphogenesis, hemodynamics, cardiovascular disease, siRNA, molecular imaging
Projects:
- Finding and evaluating novel candidate neural genes in vessel guidance and control of vascular branching morphogenesis during physiological and pathological angiogenesis
- The role of hemodynamics and neural genes in the regulation of arterial-venous vessel identity, and vessel wall remodeling in embryo development and disease
- Hypoxia signaling mechanisms controlling initiation of cardiovascular disease.
Model systems:
Zebrafish, chick embryo, mouse and human
Morpholine knockdown in transgenic zebrafish. Note the change in vascular patterning.
Research Summary:
In our lab we are interested how an embryo generates a vascular network that consists of branched arteries, veins, and lymphatic vessels. In addition we want to understand how vessels acquire their functional phenotype, the perivascular nervous innervation and the ability to regulate vascular tone.
Vascular network remodeling, angiogenesis and arteriogenesis plays an important role in the pathophysiology of ischemic cardiovascular disease, diabetes, hypertension, and cancer, which are the most common causes of mortality in western society. In the pediatric setting, improper vascular network remodelling during embryogenesis is a major cause of birth defects, and might even program for cardiovascular disease in the adult.
Although the molecular basis of endothelial cell growth is well characterized, the mechanisms controlling the formation of functional branched vascular networks remain enigmatic. We recently addressed vascular network formation using a genetic approach and molecular imaging techniques in several models including mouse, chick and zebrafish. We showed that hemodynamic forces control the global patterning of vessels and arterial-venous vessel identity by regulating genes also implied in neural guidance (Development, 2004). These genes include growth factors and their receptors, ephrinB2 and neuropilin-1, also implicated in neural guidance. In addition we discovered that neural guidance genes of the UNC family expressed in the vascular system control vascular branching, a novel concept in the field (Nature, 2004). We postulate that during evolution the vascular system has co-opted growth control mechanisms from the nervous system. At present the full repertoire of action of neural guidance genes in the vascular system remains to be uncovered. The key elements regulated by neural genes include vessel identity and branching. To substantiate this concept, our current work aims at elucidating the molecular cross-talk between 1) hemodynamics, the regulation of neural guidance genes and the establishment of vessel identity, and 2) neural genes, vessel guidance events and branching morphogenesis. For this purpose we are interested in imaging vascular morphogenesis, gene activation and hemodynamics in vivo during embryogenesis of normal and mutant mice. At present we are also establishing an in vitro system for arterial-venous differentiation based on ES cells and ES derived embryoid bodies exposed to flow, as well as promoter activity analyses of neural guidance genes.
I In addition we identified three novel genes implicated in vessel guidance, vessel branching and arteriogenesis. Using an integrative approach of genetics and molecular imaging techniques established previously in our group we want to uncover their function in cardiovascular development. One of these genes appears to play an important role in the formation of so called endothelial tip cells, the major cell type responsible for determining the direction of blood vessel growth, hence, a major therapeutic target.
Finally, we aim at translating our observations from embryo development to therapeutic strategies useful in the clinic. In this case we focus at the hypothesis that major cardiovascular diseases including hypertension and heart failure can be programmed during intra-uterine development. We recently showed that impaired fetal oxygenation, hypoxia, acting on early developmental life plays a key role. It causes aberrant remodeling of both the vascular and nervous system, progressively leading to heart failure. By interfering with specific neural guidance genes these deleterious changes can be abolished. The clinical implementation of these findings is currently investigated.
Our research is multi-disciplinary. We have extensive collaborations with clinicians including vascular surgeons, cardiologists and pediatricians. Enthusiastic candidates with interest in developmental biology, a background in molecular biology or clinicians with feeling for translational medicine are always welcome to inquire for positions.
