Blood vessels wire the entire body and act as highways for fast and efficient transport of nutrients, hormones, cells, and waste products between tissues. Depending on the organ they reside in, blood vessels show different characteristics and perform various functions. For instance, sinusoidal blood vessels, which have larger gaps between endothelial cells, allow the passage large macromolecules and help the liver to carry out its filtration function. On the other hand, specialized capillaries of the brain form a tight barrier to strictly regulate what can cross into the brain parenchyma. How the vessels of different organs (termed organotypic vasculature) acquire and maintain such differential phenotypes and functions is still a topic of investigation.
Figure 1. Vessels in different organs (Image credits Satu Paavonsalo & Sinem Karaman)
Endothelial cells in metabolic diseases
Our main research focus is studying the pathological changes that take place in the endothelial cells of the adipose tissue during obesity. Obesity and diabetes have strong links to cardiovascular diseases and endothelial cell dysfunction. However, the mechanisms how obesity and diabetes affect the vessels of adipose tissue is not yet fully known. In this project, we study these changes mainly using mouse models and molecular analyses of the isolated endothelial cells. The results from this project will have the potential to form a basis for developing novel therapies for protecting the vasculature from pathological changes and improve patient health by reducing complications of obesity and diabetes.
Obesity and overweight related comorbidities have been estimated to cost the European Union over 60 billion euros annually through healthcare costs and lost productivity. Adipose tissue lies at the crossroads of energy metabolism and it belongs to a trio of metabolically central tissues, the other two being liver and skeletal muscle. The energy surplus in obesity results in adipocyte hypertrophy and a rapid expansion of adipose tissue, which cannot be matched by the growth of new blood vessels. The resultant chronic inflammation, adipocyte death, hypoxia, and a blunted response to insulin (insulin resistance) lead to a decreased capacity of adipocytes to store lipids. Elevated free fatty-acid levels in the blood circulation then contribute to the development of other metabolic diseases, such as non-alcoholic fatty-liver disease, which is the most frequent liver disease worldwide. Hence, it is suggested that healthy expansion of adipose tissue and its proper vascularization could be protective against ectopic fat accumulation in obesity-related diseases.
Most metabolic diseases are accompanied by endothelial cell dysfunction and a loss of microvasculature, termed “capillary rarefaction”. While insulin resistance can be due to abnormal insulin signaling, it can also result from endothelial dysfunction, which leads to decreased passage of insulin and glucose to insulin-sensitive tissues. In case of adipose tissue, capillary rarefaction results in reduced tissue perfusion, tissue oxygenation, and insulin delivery to the adipocytes, impeding adipose tissue function. Thus, normalization of the adipose tissue vasculature would enable proper delivery of insulin and lipids to adipocytes and improve adipose tissue function, reducing ectopic lipid accumulation in liver and skeletal muscle. Even though endothelial dysfunction and capillary rarefaction have been observed in skeletal muscle, heart, brain and kidneys, surprisingly little is known about their molecular mechanisms and potential therapeutic targets in the adipose tissue. Therefore, we aim to shed more light onto these mechanisms by looking at the changes that occur in adipose tissue endothelial cells in obesity using a multi-omics approach.
Figure 2. Consequences of obesity-induced capillary rarefaction on tissue function. White adipose tissue (WAT), brown adipose tissue (BAT), chronic kidney disease (CKD). Image from Paavonsalo et al., Cells, 2020