Translational Vascular Medicine Branch

The Laboratory of Cardiovascular Regenerative Medicine, led by Dr. Manfred Boehm, is focused on identifying and better understanding the molecular mechanisms underlying human vascular diseases with the goal of developing new therapeutic approaches. Studies of patients with rare monogenetic vascular diseases are critical to understanding human vascular pathophysiology and have significant implications for increasing our comprehension of more common complex, polygenetic vascular diseases. The laboratory has established the Patient-Centered Vascular Translational Program to conduct research on clinically relevant questions focused on vascular injury, remodeling and repair, as well as to translate research findings into testing new therapeutic strategies. Some of the diseases the laboratory investigates include Degos disease, premature coronary artery disease, Hyper IgE Syndrome, deficiency of adenosine deaminase 2 (DADA2), STING-associated vasculopathy with onset in infancy (SAVI), arterial calcification due to deficiency of CD73 (ACDC), and cerebral autosomal dominant arteriopathy with sub-cortical infarcts and leukoencephalopathy (CADASIL).

The cause of most heart attacks and strokes, atherosclerotic plaques in blood vessel walls accumulate cholesterol primarily from circulating low-density lipoproteins (LDL), also known as bad cholesterol.  Research in the Laboratory of Experimental Atherosclerosis, led by Dr. Howard S. Kruth, focuses on understanding how cholesterol accumulates and plaque forms. Scientists have known for some time that macrophages, a type of inflammatory cell, take up LDL to become foamy, cholesterol-laden cells within plaques. Dr. Kruth and his colleagues have demonstrated an alternative mechanism for macrophage foam cell formation that does not depend on LDL modification or macrophage receptors. By this mechanism, macrophages show uptake and degradation of native unmodified LDL by receptor-independent, fluid-phase pinocytosis.  This produces cholesterol accumulation in macrophages to levels characteristic of macrophage foam cells in atherosclerotic plaques without requiring oxidative modification of LDL.  Dr. Kruth’s laboratory has shown that macrophages in atherosclerotic lesions demonstrate fluid-phase uptake of fluorescent LDL-like surrogate nanoparticles.

Cholesterol has a bad reputation, associated with cardiovascular disease, the leading worldwide cause of morbidity and mortality. Cholesterol, however, plays a vital role in normal cellular processes; hence its cellular and whole body distribution is subject to complex, dynamic regulation by circulating lipoproteins and enzymes. The Lipoprotein Metabolism Laboratory, led by Dr. Alan T. Remaley, seeks to better understand lipoprotein metabolism and to translate new insights gained from basic biochemistry, cell biology, and transgenic animal models into much-needed clinical advances in the treatment and prevention of cardiovascular disease. In a cooperative research and development agreement with an outside company, Dr. Remaley’s laboratory has been instrumental in the development of recombinant lecithin cholesterol acyl transferase (LCAT) as a possible therapy. It is currently being tested at the NIH in early stage clinical trials to treat familial LCAT deficiency (FLT) and acute coronary syndrome. Preclinical animal studies from Dr. Remaley’s laboratory have also demonstrated that a combination therapy of recombinant LCAT and HDL acts synergistically in the removal of cholesterol from cells.

The Laboratory of Vascular and Matrix Genetics is led by Dr. Beth Kozel. As a matrix biologist, vascular biologist, and geneticist, Dr. Kozel seeks to better understand the factors that influence vascular disease severity in patients with rare connective tissue disorders. Most of her work is focused on the study of two elastin insufficiency-related diseases: the neurodevelopmental condition known as Williams syndrome (WS), and isolated supravalvular aortic stenosis (SVAS), a narrowing of the aorta, the vessel that carries blood from the heart to the rest of the body. Additionally, WS and SVAS research might help shed light on high blood pressure and any other conditions associated with impaired blood flow, as well as the aging process, in which elastin breaks down very slowly over time.

The Laboratory of Vascular Thrombosis and Inflammation, led by Dr. Yogen Kanthi, studies disease mechanism in venous thrombosis with a major area of focus on regulation of venous homeostasis. Dr. Kanthi explores endogenous vasculo-protective enzymes that function at the intersection of inflammation and coagulation. He is also interested in disease pathways that are triggered by abnormal innate immune activation and cell stress responses that lead to an imbalance in coagulation and fibrinolysis. Dr. Kanthi's work utilizes human vascular cells and tissues from patients with vascular disease, primary cultures endothelial cells, and mouse models of venous thrombosis.