Vascular growth and permeability in health and disease

Time period: 2016-01-01 to 2025-12-31

Project leader: Christer Betsholtz

Funder: Swedish Research Council

Type of award: Research environment

Total fundning: 47 300 000 SEK

Over the past 10-15 years, vascular biology has transformed from a mainly medical discipline concerned with thrombosis, hypertension and atherosclerosis into a multifaceted biological science spanning from basic cell and developmental biology to human and animal genetics and novel cancer therapies. It is currently appreciated that the vasculature is more than a static “plumbing system” for gas/liquid supply and waste elimination. Instead, flow and permeability are spatio-temporally regulated with the highest precision in concert with each organ’s specific needs. We are also becoming increasingly aware of the role of blood vessel dysfunction for the development and progression of many diseases that are not classically “vascular”, including some the most common health threats in the Western world, i.e. obesity, diabetes, dementia, cancer and kidney disease. However, we still lack basic information about the molecular and cellular mechanisms in blood vessels that are attacked in these diseases, such as the regulation of vascular fluid permeability, immune cell trafficking and molecular filtration and transport. Breakdown of organ-specific vascular functions, for example the blood-brain barrier in stroke, brain trauma and brain tumors, and the progressive loss of function of the renal glomerular ultra-filter in hypertension and diabetes are common examples. The planned work aims at filling some obvious knowledge voids in this area and providing new tools and resources for future vascular biology research and to translate novel findings into clinical application when possible. The research plan includes four interrelated projects tackling fundamental questions in vascular development and function. The specific aims are:1. To provide novel insights into basic principles of vascular morphogenesis. Here, we will focus on mechanisms that prevent major arteries and veins to branch at the wrong location during development. We also will address basic principles for how immature vascular networks remodel and how the vascular cell types behave in this process. 2. To provide new insights into the regulation of vascular permeability, especially addressing a novel mechanism for “bulk transport” of fluid across the blood brain barrier (BBB). We will explore if this mechanism can be exploited to deliver drugs to the brain that are normally excluded by the BBB, and we will address the dangers (i.e., the pathological consequences) of chronic states of BBB deficiency. 3. To increase knowledge about pericytes, an obligatory cell constituent of blood micro-vessels. Pericytes are poorly defined and poorly understood, but as a result of recent breakthrough findings in our lab, we are uniquely positioned to advance the field. We will use unique animal models to address the function of pericytes in health and disease, we will explore human genetics to pinpoint disease processes that originate in pericytes, and we will develop new methods for pericyte identification and isolation and use zebrafish as a novel and powerful animal model for pericyte research. 4. To develop new tools and resources for vascular biology research. The field currently relies on a small subset of markers, reporters and drivers for imaging and cell type-specific genetic manipulation of vascular cells. Using new gene promoters and protein engineering techniques, we will devise in improved “tool bag” for vascular biology research in the mouse and zebrafish. We will apply some of these tools to generate a comprehensive catalogue of information about endothelial cells and pericytes down to the level of single cells. This resource will help delineate organ-specific vascular differentiation processes and identify vascular cell subtypes within and between organs