The endothelium- a secretory organ regulating cardiovascular physiology and pathology

Main funder

Funder's project number: 345032

Funds granted by main funder (€)

Funding program

Project timetable

Project start date: 01/01/2021

Project end date: 31/05/2022

Summary

Cardiovascular diseases rank among the most life-threatening diseases and are a continuously increasing global problem in aging populations. Endothelial dysfunction occurs in many diseases, but endothelial cells (ECs) are not often considered as therapeutic targets, even though in most cases heart problems arise secondary to vascular defects. It was shown recently that capillary ECs in different tissues are endowed with distinct structural, phenotypic and functional properties. Furthermore, ECs were demonstrated to regulate tissue regeneration and growth in liver and lungs by secreting angiocrine factors, which then act on neighbouring cells. However, almost nothing is known about the cardiac EC secretome (cardiac angiocrines) in response to physiological or pathological stimuli. Aging, obesity and physical inactivity are major risk factors for both cardiovascular and metabolic diseases, which are often closely linked. Adipokines, myokines and cardiokines produced by adipose tissue, skeletal muscles and the heart are distributed throughout the body via the circulation, and the first cell type to encounter them is endothelial cell (EC). They in turn respond to these stimuli by producing angiocrine factors, which could be either harmful or protective to the cardiomyocytes (CMC). The aim of this project is to identify these angiocrines as potential therapeutic targets for prevention and treatment of cardiovascular diseases. ECs from the heart will be isolated and the changes in transcriptomes will be analysed by RNA sequencing. Genes whose expression differs due to the treatments will be analysed by publicly available algorithms to predict the subset of genes that are likely secreted. The hits will be verified at the protein level and their function and relevance will be further studied using cellular co-cultures and gene-modified animals and gene therapy approaches. To verify the translational potential of the results, I will collect material from cardiac biopsies and from cardiac transplantations to isolate ECs and investigate their expression profiles. The Research Programs Unit at the University of Helsinki will provide excellent facilities and critical mass for discussion and ideas for conducting all parts of the planned project, and several national and international collaborators are also involved. Successful identification of angiocrine(s) that can modify CMC function in the disease settings would open up completely new avenues for the heart failure treatment options.

Principal Investigator

Primary responsible unit

Follow-up groups

Profiling area: Physical activity through life span (University of Jyväskylä JYU) PACTS