Interview with Holger Gerhardt

In March the BIH Professor for Experimental Cardiovascular Research Holger Gerhardt and his team were awarded the Paper of the Month. We talked to him about the paper and its research:

What is at the focus of your research?

Our „integrative vascular biology lab“ aims to understand the fundamental principles and regulatory mechanisms that establish and maintain functional blood vessel networks. We focus on the building blocks of blood vessels, the endothelial cells, that form and shape all vessels in our body, and ask how these arise, acquire specific functions and coordinate their behavior such that each organ receives the optimal network of vessels to support the required supply of oxygen and nutrients. Our work is motivated by the fact that cardiovascular disease is the number one reason for premature mortality and decreased quality of life in humans. Understanding how endothelial cells shape and adapt blood vessel networks, as well as when, where and how these processes fail during disease progression promises to guide developments for prevention and advanced therapies in cardiovascular disease.

What is the core message of your publication and how does your study differ from the work of other scientists in this field?

The central message of our present manuscript entails the discovery of a novel mechanism of blood vessel stabilization during development. Primary cilia are evolutionary conserved flexible and sometimes motile appendages of almost all cells in our body, which can sense chemical and mechanical signals. Our work investigated the distribution and function of these cilia in endothelial cells during development of the mouse retinal blood vessels. Through a combination of advanced imaging, genetic manipulation, and computer simulation of blood flow and the forces it exerts on the endothelial cells, we were able to identify that these cilia prevent vessels that receive lower blood flow from regressing. Previous studies had identified that endothelial cells in fish are present especially in conditions of low blood flow and that they function as sensors of blood flow leading to calcium signals in endothelial cells. Our work uncovered that endothelial cells that possess cilia are vastly more sensitive to a stabilizing chemical present in the blood stream, thereby preventing premature and widespread vessel regression. Given that vessel regression is a major complication in hypertension and various vascular disease including vascular dementia, we hope our findings will lead the way towards understanding mechanisms and potential treatments of these vascular complications.

Which cooperation partners have contributed to the publication? Who was significantly involved?

This publication originated from ideas developed in our Integrative Vascular Biology Laboratory and was strongly driven by the first and corresponding author Dr. Anne-Clemence Vion. It involved cooperation between several members of our lab at the MDC, and external cooperation with Miguel Bernabeu at Edinburgh University for flow modelling, as well as cooperation with the team of Pierre-Emmanuel Ratou, Inserm, Paris for analysis of one of the mouse mutant lines lacking endothelial cilia.

What are the next steps planned for the project and what are the possible implications of your results for patients?

As vessel regression can drive or aggravate hypertension and can cause various vascular disease processes, we will continue to investigate the pathophysiological effects of cilia loss, as well as study the detailed molecular mechanisms involved in vessel stabilization. It is possible that cilia defects or their loss occurs prior to loss of vessels in aging patients, and we will aim to develop methods to investigate this hypothesis, and to study possibilities of maintaining cilia function in adult.