With increasing age, blood vessels become stiffer and more calcified. In the latter years of the human lifespan, the process of vascular aging accelerates. The reason that blood vessels lose their youthful elasticity and ability to retard the deposition of calcium precipitously later in life is poorly understood. Ectonucleotidases are found on the surface of endothelial cells which line the inner surface of blood vessels, vascular smooth muscle cells, and leukocytes. The ectonucleotidase CD39 is responsible for cleaving ATP and ADP to form AMP, and subsequently, CD73 is responsible for generating adenosine from AMP. Since ATP and ADP are pro- inflammatory and act in a paracrine fashion, I hypothesize that ectonucleotidase activity plays a role in the vascular stiffness and calcification that occurs as a consequence of age. This is supported by my preliminary data in wild type (C57BL/6) mice, which demonstrates CD73 protein levels declined with age (up to 24 months) in the heart and kidney. This is also supported by preliminary data in mice and human tissues demonstrating that loss of CD73 expression promoted expression of the transcription factor Runx2, which is critical for osteogenesis. We hypothesize that loss of ectonucleotidase expression with age could have deleterious consequences on the vessel wall, resulting in an environment which promotes vascular calcification and stiffness. Since the role of ectonucleotidases in vascular aging is unknown, we will elucidate mechanisms which mediate age-dependent vascular calcification through the following aims.
Aim 1 : We will determine how age-dependent decline in vascular ectonucleotidase expression renders vessels susceptible to vascular calcification and fibrosis in a murine model.
Aim 2 : We will determine how ectonucleotidase activity mitigates arterial fibrosis and stiffness.
Aim 3 : We will determine if ectonucleotidase expression plays a role in age-driven human coronary artery calcification. Achievement of these aims will elucidate the role of ectonucleotidases in age-dependent vascular calcification and stiffness in mice and humans. The mechanistic insights obtained from these experiments will define my future investigative direction and serve as a foundation for a subsequent RO1 application as an independent investigator studying vascular biology and aging.
There is an increase in cardiovascular disease with age, stemming from the fact that as blood vessels age, they become more calcified and stiff. Over time, these changes impair critical organ function (e.g. brain, heart, and kidneys). The aim of this research is to understand how proteins called ectonucleotidases, which reduce inflammation and the tendency for clot formation, influence how blood vessels age. Gaining this knowledge will hone future strategies to treat vascular disease.
