Cardiovascular disease is the leading cause of mortality and ischemic heart disease is a major cause of death worldwide. Coronary vessels that nourish the heart develop from three main sources, the endocardium on the inner surface of the hearts blood-filled chambers being one of the major contributors. In normal conditions, the adult heart can no longer generate new blood vessels from the endocardium, because the endocardium-to-coronary vessel transition is blocked by a connective tissue wall beneath the endocardium.
In a recently published study an international team led by researchers of the Wihuri Research Institute and the University of Helsinki show that the VEGF-B growth factor can be used to activate the growth of vessels inside of the heart during cardiac ischemic damage.
This novel finding opens the possibility that vessels emerging from the inner side of the heart could be further developed for the treatment of myocardial infarction, which results from insufficient delivery of oxygen to cardiac tissue. In normal conditions, blood nourishes the adult heart through coronary vessels.
The largest coronary vessels are located on the heart surface, and their branches dive into heart muscle to deliver oxygen-rich blood into the inner parts of the heart. Occlusion of the largest coronary arteries due to atherosclerosis and blood clotting is commonly treated by catheter-mediated reopening. However, any remaining blood clots in the small coronary vessels inside the heart cannot be removed, which can lead to local infarction of the heart muscle. Due to the long distance of blood delivery to the inner myocardium and pressure conditions during heartbeat, infarctions of the inner myocardium are particularly common in patients with hypertension.
Increasing coronary vessels by using VEGF-B
VEGF-B (vascular endothelial growth factor) belongs to a family of growth factors that regulate the formation of blood- and lymphatic vessels. Professor Ulf Eriksson at the Karolinska Institute together with Academy Professor Kari Alitalo were the first to isolate the VEGF-B gene in 1996. Together with the research group of Professor Seppo Ylä-Herttuala, they previously showed that VEGF-B can induce the growth of coronary vasculature.
Earlier attempts to utilize another growth factor gene, VEGF-A, to grow new vessels in the heart have failed, mostly due to the leakiness of the vessels and increased inflammation caused by VEGF-A, but not by VEGF-B.
“The highlight of this study is that by using VEGF-B, we were able to induce the growth of new vessels from the inner surface of the cardiac ventricles during heart development, and again in adult mice, in the ischemic inner parts of the heart," says MD, PhD Markus Räsänen.
“Such kind of a novel “bypass route” could open translational therapeutic possibilities for the treatment of coronary artery disease. Re-activation of the embryonic vessel growth program in adult endocardium could be a new therapeutic strategy for cardiac neovascularization after myocardial infarction. For possible future clinical use, the function of these vessels and their blood flow has to be further studied to ensure that they really increase transport of oxygen and nutrients into the cardiac muscle," confirms the Director of Wihuri Research Institute, Academy Professor Kari Alitalo.
This research was conducted by the Wihuri Research Institute, University of Helsinki, University of Uppsala, Karolinska Insitute, University of Bern and University of Shanghai. Funding was obtained from Wihuri Research Institute, Finnish Academy, Finnish foundation for cardiovascular research, Paavo Nurmi Foundation, Paulo Foundation, Aarne Koskelo Foundation, Biomedicum Helsinki Foundation and Emil Aaltonen Foundation.
Reference: Markus Räsänen, Ibrahim Sultan, Jennifer Paech, Karthik Amudhala Hemanthakumar, Wei Yu, Liqun He, Juan Tang, Ying Sun, Ruslan Hlushchuk, Xiuzheng Huan, Emma Armstrong, Oleksiy-Zakhar Khoma, Eero Mervaala, Valentin Djonov, Christer Betsholtz, Bin Zhou, Riikka Kivelä and Kari Alitalo. VEGF-B promotes endocardium-derived coronary vessel development and cardiac regeneration, Circulation, 2020. DOI: 10.1161/CIRCULATIONAHA.120.050635.
Markus Räsänen, MD, PhD, Wihuri Research Institute, University of Helsinki
Kari Alitalo, Academy Professor, University of Helsinki, director, Wihuri Research Institute