Cardiometabolic diseases, such as cardiovascular disease, type 2 diabetes and hypertension, are the number one cause of death in the western world; thus they present an urgent need for novel therapies. Despite recent progress in the treatment options for cardiometabolic diseases, the clinical prognosis of e.g. heart failure is currently worse than prognosis of most cancers. Blood vessels are essential in all tissues for the delivery of oxygen and nutrients. Recent studies have demonstrated that blood vessels are much more than an inert conduit for blood flow. Instead, endothelial cells lining the vessels are active regulators of tissue growth, metabolism and regeneration.
We want to understand how the interaction between endothelial cells and other cell types in the tissues is regulated and how the intercellular communication is disturbed in cardiometabolic disease. The goal of our studies is to enhance understanding on the role of vasculature in cardiometabolic disease and in mediating the health benefits of exercise. Eventually, we aim to identify novel therapeutic targets in endothelial cells for cardiometabolic disease.
We are also interested in skeletal muscle stem cell differentiation and skeletal muscle physiology and pathology, with a special focus on the role of the PROX1 transcription factor. Our aim is to understand the role and function of PROX1 in skeletal muscle physiology and in rhabdomyosarcoma, which is a highly malignant pediatric cancer with myogenic features.
VASCULAR BIOLOGY IN CARDIOMETABOLIC DISEASES
Endothelial cells in different organs express a unique combination of transcription factors, angiogenic growth factors, adhesion molecules and chemokines. The organotypic vasculature reflects the varying needs of different organs, for example, oxygen and nutrient supply. In response to various stimuli, endothelial cells secrete a set of proteins, which can act on the neighboring cells or distant tissues. Adult humans have approximately 100 000 km of blood vessels, which makes the vasculature one of the largest “endocrine organs” in the body.
Our group has a specific interest in the crosstalk between endothelial cells and myocytes in the heart and skeltal muscle. We want to know how this interaction 1) is regulated in healthy tissues and during physiological growth, 2) affected by aging, obesity, heart failure and exercise, and 3) contributes to the development of cardiometabolic diseases and 4) could be targeted pharmacologically to mimic the health benefits of exercise.
REGULATION OF SKELETAL MUSCLE PHYSIOLOGY AND PATHOLOGY BY THE PROX1 TRANSCRIPTION FACTOR
After damage, skeletal muscles have a remarkable capacity for regeneration. We have shown that the PROX1 transcription factor, which regulates stem cell behavior in various healthy and malignant tissues, is essential for slow muscle fiber type characteristics and stem cell differentiation in skeletal muscle. Interestingly, several genome-wide association studies have identified PROX1 as a candidate gene for type 2 diabetes in various populations, thus we explore the mechanisms and relationships between PROX1 and muscle metabolism. Our results on PROX1 mediated regulation of muscle stem cell differentiation improve current understanding of muscle regeneration and satellite cell function, as well as the role of PROX1 in rhabdomyosarcoma. Our recent findings demonstrated that PROX1 is an essential mediator of rhabdomyosarcoma growth, stemness and myogenic properties.
ANGIOGENESIS IN COMBATTING MUSCLE WASTING
Cachexia and sarcopenia are increasing health problems among the aging population and in many chronic illnesses. Several pre-clinical research and clinical trials have tested different options to increase muscle mass and to prevent muscle loss. However, increasing muscle mass has led to severe side-effects on oxidative metabolism and exercise tolerance. We have previously demonstrated that angiogenesis induces physiological-type hypertrophy in the heart. Our current aim is to induce concomitant angiogenesis and muscle growth to promote muscle growth further and to improve the metabolic function of muscles via enhanced vasculature.
PROX1 transcription factor controls rhabdomyosarcoma growth, stemness, myogenic properties and therapeutic targets. Gizaw NY, Kallio P, Punger T, Gucciardo E, Haglund C, Böhling T, Lehti K, Sampo M, Alitalo K, Kivelä R. 2022, Proc Nat Acad Sci, 119(49):e2116220119.
Cardiovascular disease risk factors induce mesenchymal features and senescence in mouse cardiac endothelial cells. Hemanthakumar KA, Fang S, Anisimov A, Mäyränpää MI, Mervaala E, Kivelä R.2021, Elife 10:e62678.
VEGF-B promotes endocardium-derived coronary vessel development and cardiac regeneration. Räsänen M, Sultan I, Paech J, Hemanthakumar KA, Yu W, He L, Tang J, Sun Y, Hlushchuk R, HuanX, Armstrong E, Khoma OZ, Mervaala E, Djonov V, Betsholtz C, Zhou B, Kivelä R, Alitalo K. 2021, Circulation, 143: 65-77.
Flow-Induced Transcriptomic Remodeling of Endothelial Cells Derived From Human Induced Pluripotent Stem Cells. Helle E, Ampuja M, Antola L, Kivelä R. 2020, Front Physiol, 11:591450.
Angiogenesis and angiocrines regulating heart growth. Hemanthakumar KA, Kivelä R. 2020, Vasc Biol. 2(1): R93-R104.
Endothelial Cells Regulate Physiological Cardiomyocyte Growth via VEGFR2 -Mediated Paracrine Signaling. Kivelä R, Hemanthakumar KA, Vaparanta K, Robciuc M, Izumiya Y, Kidoya H, Takakura N, Peng X, Sawyer DB, Elenius K, Walsh K, Alitalo K. 2019, Circulation, 139:2570-2584.
Cardiomyocyte—Endothelial Cell Interactions in Cardiac Remodeling and Regeneration. Talman V, Kivelä R. 2018, Front Cardiovasc Med, 5:101.
Prevention of chemotherapy-induced cachexia by ACVR2B ligand blocking has different effects on heart and skeletal muscle. Hulmi JJ, Nissinen TA, Räsänen M, Degerman J, Lautaoja JH, Hemanthakumar KA, Backman JT, Ritvos O, Silvennoinen M, Kivelä R. 2018, J Cachexia, Sarcopenia, Muscle, 9:417-432.
The transcription factor Prox1 is essential for satellite cell differentiation and muscle fibre type regulation. Kivelä R, Salmela I, Nguyen YH, Petrova TV, Koistinen HA, Wiener Z, Alitalo K. 2016, Nat Commun, 7: 13124.
VEGF-B/VEGFR-1 induced expansion of adipose microvasculature counteracts obesity and related metabolic complications. Robciuc M, Kivelä R, Williams IM, de Boer JF, van Dijk TH, Elamaa H, Tigistu-Sahle F, Molotkov D, Käkelä R, Eklund L, Wasserman DH, Groen AK, Alitalo K. 2016, Cell Metab, 23: 712-724.
VEGF-B-induced vascular growth leads to metabolic reprogramming and ischemia resistance in the heart. Kivelä R, Bry M, Robciuc MR, Räsänen M, Taavitsainen M, Silvola JM, Saraste A, Hulmi JJ, Anisimov A, Mäyränpää MI, Lindeman JH, Eklund L, Hellberg S, Hlushchuk R, Zhuang ZW, Simons M, Djonov V, Knuuti J, Mervaala E, Alitalo K. 2014, EMBO Mol Med 6: 307-321.
Minna Ampuja, Postdoctoral researcher
Liina Uusitalo-Kylmälä, Postdoctoral researcher
Alfredo Ortega-Alonso, Postdoctoral researcher
Oiva Arvola, Postdoctoral researcher
Kalle Kolari, Postdctoral researcher
Nebeyu Gizaw Yosef, PhD student
Aino Männistö, PhD student
Kialiina Tonttila, PhD student
Erik Tolvanen, Master’s student
Jacob Andersson, Medical student
Erik Niemi, Master’s student
Sabina Selenius, PhD student
Sami Myllykangas, Medical student
Aliisa Auvinen, medical student
Ilse Paetau, Lab manager
Karthik Amudhala Hemanthakumar, PhD student
Emmi Helle, Clinical research fellow
Siiri Toropainen, Master student
Laura Antola, Master student
Tatjana Punger, Master student
Elviira Hyvönen, Medical student
Charlotte Gouret, Undergraduate student
Maxime Laird, Undergraduate student
Manon Gruchet, Undergraduate student
Kirsi Mattinen, Laboratory technician