Vascular Growth Factor

Vascular growth factors and their inhibitors hold significant potential for treating a wide range of human diseases. Our research focuses on their preclinical and translational applications, with the goal of restoring homeostasis and improving tissue function in cardiovascular and other diseases.

Our goal is to develop novel therapeutic approaches by leveraging insights into the biology of vascular endothelial growth factors (VEGFs), angiopoietins (Ang), and the processes of blood vessel growth (angiogenesis) and lymphatic vessel growth (lymphangiogenesis). Current treatments for cardiovascular diseases and cancer are often insufficient or unsuitable for many patients, highlighting the urgent need for new therapies. While inhibition of blood vessel growth is already used in clinical practice, its success has been limited. Conversely, attempts to stimulate angiogenesis and the development of collateral arteries (arteriogenesis) to treat tissue ischemia have largely been unsuccessful.

We investigate the functions and translational potential of vascular growth factors and receptors that we have discovered. Our findings have led to clinical trials for lymphedema and eye diseases, and our discovery of a meningeal lymphatic system has opened the door to analyzing its role in central nervous system diseases. We utilize molecular genetic models, functional genomics, single-cell transcriptomics, proteomics, and metabolomics, along with viral vectors for gene delivery and biologics that block growth factor–receptor interactions. These cutting-edge technologies enable us to advance treatments for cardiovascular and other diseases.

Our work on vascular endothelial growth factors and related pathways opens new opportunities to explore therapeutic options for diseases in which the vasculature plays a critical role.

Members of the VEGF family, consisting of five mammalian proteins, are key regulators of blood and lymphatic vessel development. VEGFs promote angiogenesis and lymphangiogenesis by activating VEGF receptor (VEGFR) tyrosine kinases in endothelial cells. In both physiological and pathological angiogenesis, hypoxia triggers VEGF production, which stimulates vessel growth primarily through VEGFR-2, while VEGFR-1 mainly functions as a decoy receptor with minimal signaling activity. Although VEGF-blocking antibodies have been successfully used in cancer therapy, efforts to use VEGF for proangiogenic therapy in tissue ischemia have been limited by VEGF-induced vascular leakage and abnormal vessel growth.

Since its discovery 30 years ago, we have demonstrated that VEGF-B can protect against myocardial infarction by expanding the coronary vasculature and increasing cardiac muscle mass. Moreover, VEGF-B expression is reduced in failing hearts. These findings suggest that VEGF-B therapy offers a unique opportunity to remodel the myocardial vasculature and enhance cardiac blood flow. Our studies also indicate that VEGF-B can improve glucose and insulin tolerance by expanding the vasculature in adipose tissue.

In adults, VEGFR-3, the receptor for VEGF-C and VEGF-D, is expressed primarily in the lymphatic vasculature, where VEGF-C regulates lymphatic vessel growth. However, VEGFR-3 is also expressed in blood vessels during angiogenesis. In 2015, we discovered a meningeal lymphatic vessel system surrounding the brain. Subsequent studies are investigating the roles of VEGF-C/VEGFR-3 in cerebrovascular dynamics, cerebrovascular fluid drainage, and cellular trafficking in both homeostasis and disease models, including neuroinflammatory and neurodegenerative conditions.

We discovered the endothelial Tie receptor tyrosine kinase (now known as Tie1) in 1992. It is now established that angiopoietins (Ang1, Ang2, and Ang4), ligands of the Tie1/2 receptor complex, are essential for vascular stabilization following angiogenesis. We have demonstrated that the Tie2 receptor is atheroprotective, that Ang2 blockade reduces neuroinflammation and that Ang2 mutations are linked to human lymphedema. Furthermore, we showed that VEGF-C mediated lymphangiogenesis requires autocrine Ang2 signaling in lymphatic endothelial cells. Given its unique role in vascular stability, the Ang-Tie signaling pathway represents a promising therapeutic target for diseases characterized by vascular dysfunction.