Developmental vascular biology
Understanding how blood vessels form — and what happens when that process goes awry — could lead us to better tools to help kids with vascular conditions such as hemangiomas and solid tumors.
What is developmental vascular biology research?
The developmental vascular biology program, led by Ramani Ramchandran, PhD, investigates the basic mechanisms of blood vessel formation in vertebrates and how those vessels contribute to diseases. Our researchers study developing zebrafish and mouse embryos to gain insights into vascular conditions associated with children, such as hemangiomas and solid tumors.
We study cells called angioblasts, which eventually differentiate into arteries or veins. The basic mechanisms of this process often are deregulated in disease, so better understanding vessel formation is critical to generating new treatments for conditions affected by deregulated vessel growth.
During development, blood vessels adapt to the specific needs of the organ they supply. For example, in the lungs, the vasculature becomes highly specialized to provide efficient gas-exchange by participating with alveoli. Development of lung alveoli requires complex interactions among blood vessels, other specialized cells and the extracellular matrix. Defects in any one of these elements will adversely affect alveolar development and can lead to conditions such as emphysema and infant bronchopulmonary dysplasia.
In addition to studying blood vessel formation, our researchers are also developing tools for performing drug screens using zebrafish embryos, which will identify targets and potential drug leads for treating pediatric vascular conditions.
Angioblast development in vertebrates
Endothelial precursor cells, also known as angioblasts, are specified from lateral mesoderm cells in the developing vertebrate embryo. The intermediate steps necessary for the angioblast to form arteries and veins are not clear. The Ramchandran laboratory studies the signals and processes involved in the different steps of angioblast development in a developing embryo using a variety of cell biology, genetic and molecular approaches.
Role of axon guidance genes in vascular development
Vessels and nerves are branching networks that often lay side by side in a developing embryo. Mechanisms governing branching morphogenesis are shared both at the cell surface and the intracellular levels in endothelial cells and axons respectively. The Ramchandran lab is interested in understanding the molecular mechanisms that guide an endothelial cell to its target using clues from the axon guidance system. We study one member of the axon guidance family, roundabout4 (robo4), and its role in this process.
Translational disease models and drug discovery
Vessel growth is tightly regulated during development. Any imbalance in this regulation often is associated with disease. For example, tumor growth is dependent on neo-vessel growth or angiogenesis. The Ramchandran laboratory is developing disease models in fish using a variety of genetic and molecular approaches that will eventually be used for drug screening. We use computational small molecule and conventional screening approaches to target mutant protein vs. wild type protein in the vasculature. Using such approaches we have identified candidate small molecules against targets mutated in human vascular anomaly disease. The efficacy of some compounds is in the nanomolar range, which is being further developed as therapeutics.
In addition, the Ramchandran lab has taken a leading role in forming a drug discovery consortium in Southeastern Wisconsin that works toward a common goal of generating affordable therapeutics that will benefit the health of the local communities and beyond.
Cell surface receptors affecting endothelial migration
Angiogenesis, the formation of new vessels from a preexisting network, depends proper mobilization of blood endothelial cells. Our lab uses a combination of molecular genetic and cell biology approaches to study cell-surface control of endothelial cell motility. In one project, we study the impact of endothelial ephrin-B2 in lung alveolar development. The abnormal lung development of mice expressing mutant ephrin-B2 provides an opportunity to investigate the phenomenon of alveolar initiation from a cell and developmental biology point of view. In a second project, we are evaluating a poorly understood novel cell-surface protein ECSCR, which is selectively expressed in endothelial cells and influences endothelial migration and proliferation.