Angiogenesis and lymphangiogenesis are regulated by vascular endothelial growth factor (VEGF) ligands and receptors under both physiological and pathological conditions. Endocytosis and intracellular transport of receptor complexes fine-tunes endothelial cell responses to VEGF, and these events are coordinated by endocytic adaptor proteins such as epsins and Dab2. Using mice with inducible endothelial-specific epsin 1 and 2-deficiency (EC-iDKO), we have shown that the loss of these adaptor proteins increases angiogenesis in the developing or injured retina and brain by permitting activated VEGF receptor (VEGFR2) recycling to the cell surface.

Recently, we used scRNA-seq and bioinformatic analyses to determine the source of endothelial cells responsible for increased angiogenesis in the developing mouse brain. We have identified a non-committed cell population that expresses endothelial markers in EC-iDKO brains. Computational RNA velocity analyses indicates that neuronal cells transition into non-committed cells in WT mice; however, this transition increases in EC-iDKO mice. In adult mice subjected to stroke, epsin deficiency promotes neovascularization and improves motor function in affected mice. Our findings advance our understanding of cell plasticity and highlight the therapeutic potential of increasing angiogenesis through epsin inhibition for stroke.


Atherosclerosis is the leading cause of life-threatening myocardial infarction, ischemic stroke, and peripheral arterial disease in the United States. Dyslipidemia remains a major risk factor for developing atherosclerosis despite lipid-lowering therapies and prevention programs. This is, in part, due to overwhelming arterial inflammation that drives the transition from a stable to vulnerable and rupture-prone atherosclerotic plaque. The lack of effective therapies to lower circulating cholesterol while curbing arterial inflammation during plaque progression presents an opportunity to develop innovative medicines for this devastating disease. Understanding the causative molecular mechanisms responsible for dyslipidemia and arterial inflammation should provide for the rapid development of more potent therapeutic approaches.

Our research has centered on determining the influence of endothelial and macrophage epsins on atherosclerosis. We showed that epsins are upregulated in plaques in mouse models of atherosclerosis and human atherosclerotic lesions. Deletion of epsins in the endothelium or in macrophages results in attenuation of atherogenesis. Mechanistically, we discovered epsins escalate arterial inflammation by increasing adhesion molecule expression, enhancing monocyte recruitment, and hindering efferocytosis. More recently, we created a liver-specific deficiency of epsins in atherosclerotic mice and found that atherogenesis was inhibited and accompanied with diminished blood cholesterol and triglyceride levels. Targeting epsins, their binding partners, and downstream targets represents an attractive therapeutic approach to treat chronic vascular inflammation and dyslipidemia in atherosclerosis.


Diabetes affects over 30 million people in the United States and costs a staggering $327 billion a year in direct medical costs and lost productivity. Diabetes adversely affects blood vessels as hyperglycemia and insulin resistance are key players in the development of atherosclerosis, retinopathy, and peripheral artery disease. Our goal is to understand how chronic hyperglycemia impairs vascular endothelial cell function and identify molecular targets that will form the basis for new therapeutic approaches to treat the vascular complications of diabetes.

Vascular endothelial growth factor receptors (VEGFR2/3) are critical regulators of blood vessel growth or angiogenesis. These receptors are reduced in the endothelium of diabetic patients, resulting in inadequate angiogenesis. We have shown that diabetic conditions induce expression of autophagosome proteins and promote degradation of VEGFR2/3. In particular, we identified the protein Unc-51-like autophagy activating kinase 1 (Ulk1) as an important inhibitor of angiogenesis by stimulating autophagosome formation. Loss of endothelial Ulk1 elevated VEGFR2/3 levels and enhanced angiogenic responses. We also showed the Forkhead box transcription factor (FoxO1) controls expression of endothelial Ulk1 in diabetic models in vivo and in vitro and a deficiency of endothelial FoxO1 inhibits autophagosome formation, suggesting that targeting FoxO1 may prevent the vascular complications of diabetes.


The lymphatic system maintains tissue fluid homeostasis, immune surveillance, and intestinal lipid absorption. Emerging evidence supports an essential role for this system in mitigating a variety of human disorders including lymphedema, heart disease, metabolic syndrome, stroke, and tumor metastasis. Recent work suggests that defective or insufficient lymphatic function hinders restoration of normal cardiac function after myocardial infarction (MI). Conversely, enhanced lymphangiogenesis underscores the improved cardiac function post MI by promoting resolution of myocardial edema, diminishing inflammation, and strengthening cardiomyocyte regeneration and survival.

These findings indicate that stimulation of lymphangiogenesis in an infarcted heart could be a valuable therapeutic approach to improve cardiac function and prevent adverse cardiac remodeling. In addition, congenital defects in lymphatic development or by acquired occlusion of lymphatic vessels resulting from infection, radiation therapy, and surgical lymph node removal are underlying causes for lymphedema. In the United States, lymphedema is a clinical complication in cancer patients. Our goal is to uncover critical regulators that govern lymphatic function, with the hope of offering new therapeutic targets to combat various diseases.