Role of VEGF Signaling in Vascular Permeability and the Zebrafish Disease Model

The Tumor Angiogenesis and Vascular Biology Lab uses a zebrafish disease model to study vascular endothelial growth factor (VEGF) signaling in vascular permeability.

The zebrafish (Danio rerio) has emerged as a powerful model organism for the study of vertebrate vascular biology, being well-suited to both developmental and genetic analysis. Large-scale genetic screens have identified hundreds of mutant phenotypes, many of which resemble human clinical disorders.

Dr. Mukhopadhyay's lab employs tools such as CRISPR, TALEN, morpholinos and transgenesis to explore the VEGF-mediated molecular mechanisms and their roles in vascular permeability and related diseases.

Vascular permeability plays an integral role in the pathology of cardiovascular disease, stroke and cancer. VEGF induces vascular permeability in ischemic diseases and cancer, leading to many pathophysiological consequences.

The molecular mechanisms by which VEGF acts to induce hyperpermeability are poorly understood, and there are no in vivo models that easily facilitate real-time, genetic studies of vascular permeability.

The Tumor Angiogenesis and Vascular Biology Lab developed a heat-inducible VEGF transgenic zebrafish model through which vascular permeability can be monitored in real time.

Using this approach with morpholino-mediated gene knock-down and knockout mice, the lab identified a novel role of phospholipase Cβ3 as a negative regulator of VEGF-mediated vascular permeability by regulating intracellular Ca2+ release.

The lab's results suggest an important effect of PLCβ3 on vascular permeability and provide a new model with which to identify genetic regulators of vascular permeability that are crucial to several disease processes.