Ram Kumar Subramanyan

PIBBS MENTOR

Assistant Professor of Surgery and Pediatrics

Research Topics

Cardiovascular morphogenesis, vessel maturation, tumor angiogenesis

Research Overview

The over-arching research goal of my lab is to understand the biology of membrane proteins expressed on the surface of cardiovascular progenitor cells. In particular, we study the role played by these proteins in endocardial control of cardiac morphogenesis and in vascular maturation at sites of physiologic and pathologic angiogenesis. This work covers basic mechanistic study of cardiovascular morphogenesis and the translational application of principles so discerned towards improving angiogenesis at sites of ischemia as well as limiting angiogenesis in disease states such as cancer. To elucidate a few examples,

i. Our previous work has shown that the Delta-like-4 ligand (DLL-4) of the Notch receptor pathway is only the second protein known so far that is required in a dosage-sensitive manner for vascular maturation, in that haploinsufficiency has a profound vascular phenotype and is often embryonically lethal. Mice with knock-out and overexpression of DLL4 also show cardiac defects that have not been fully characterized. There is evidence to suggest a strong role for the Notch receptors in endocardial cushion formation, ventricular cardiomyocyte proliferation and outflow tract formation. As the only endocardial-specific ligand in the Notch pathway and given its already critical role in vascular morphogenesis, the natural question to be answered is how DLL-4 controls cardiac morphogenesis.
ii. Whereas proteins like VEGF, FGF and PDGF are critically required for the initiation of angiogenesis, it has been documented that these proteins alone are incapable of effective angiogenesis, especially at sites of ischemia. My previous work, and those of others worldwide, has shown the importance of vessel maturation proteins in regulating angiogenesis, establishing vascular hierarchy and integrating newly formed vessels into the parent circulation. Modulation of the expression of these vessel maturation proteins at sites of ischemia has the potential to augment neovascularization and improve perfusion and, consequently, end-organ recovery.
iii. The absolute requirement for vessel maturation proteins to form stable and competent vasculature provides an opportunity to limit angiogenesis in vascular proliferative disorders, especially cancer. My PhD thesis work with the protein Erythropoietin producing hepatoma receptor B-4 (EphB4) showed that apart from its important role in tumor vascularization, aberrantly expressed EphB4 also provides direct survival signals to tumor cells. Strategies aimed at interrupting EphB4 signaling can significantly impact tumor survival and metastases, and has profound therapeutic potential.

My lab studies cardiovascular generation and maturation in transgenic mouse models and applies principles of angiogenesis to improve end-organ recovery from ischemia. To this extent, we have fostered fruitful relationships with experts in angiogenesis and cardiac embryology in the University. In addition, we have partnered with biomedical engineers at USC Imaging Center in developing cardiovascular imaging modalities in mice that will benefit all researchers working in this field. I have also partnered with experts in Portugal to set up joint programs to study the molecular signals in cardiac morphogenesis. Lastly, we study various oncology models both in vitro and in vivo to understand the role played by vessel maturation proteins in tumor biology.