This application for a career development award to help establish a clinician scientist career for the applicant in uremic vascular biology with specific attention to vascular calcification. Vascular calcification is a common problem in patients with end stage renal disease (ESRD) that is receiving increased attention. Calcification has been thought to be solely the result of circulating calcium and phosphate concentrations that exceed the levels of spontaneous precipitation but it is now clear that vascular smooth muscle is an active participant in this process. Specifically, smooth muscle produces inhibitors of calcification such as pyrophosphate, osteopontin and matrix GLA protein but vascular calcification also may accompanied by ectopic bone formation (osteogenic differentiation). The origin and pathogenetic role of osteogenic cells in vessels are not clear. It is also well established that moderate doses of vitamin D in uremic rats can dramatically promote vascular calcification, but the mechanisms of deleterious effects of vitamin D on vascular mineralization have not been explored. Using rat and mouse uremia models, as well as in vitro model of vascular calcification the applicant will investigate temporal and spatial relationships between expression of inhibitory and osteogenic genes and calcium phosphate deposition, to shed light on relative importance of osteogenic differentiation versus deficiency of inhibitory factors in uremic vascular calcification. He will then investigate the origin of osteogenic cells in vessels. The goal will be accomplished by bone marrow and aorta transplantation to study vascular calcification in chimeric animals where bone marrow or portions of aorta have different genetic origins. This will allow differentiating recipient from donor derived osteogenic cells in calcified vessels and resolve their origin (local VSMC versus circulatory osteogenic progenitors). Mechanisms of vitamin D effects on uremic vessel will be studied next. Vascular calcification will be induced by injecting calcitriol in wild type uremic chimeric mice with vitamid D receptor deficient (VDR-/-) portions of abdominal aorta (chimera created by surgical transplantation). Osteogenic and inhibitory gene regulation with vitamin D will be studied in vessels in vivo and in vitro.
Vascular calcification is highly prevalent in chronic kidney disease (CKD) and end stage kidney disease (ESRD) patients and contributes to very high cardiovascular morbidity and mortality in this group. Currently, the treatment is aimed on reducing the blood phosphorus concentration in is not achievable in all patients. Investigating and understanding the molecular mechanisms of vascular calcification will definitely help to design new ways of prevention and treatment of vascular calcification and highly relevant clinically.
|Lomashvili, Koba A; Manning, Kelly E; Weitzmann, M Neale et al. (2017) Persistence of Vascular Calcification after Reversal of Uremia. Am J Pathol 187:332-338|
|Lomashvili, Koba A; Narisawa, Sonoko; Millán, Jose L et al. (2014) Vascular calcification is dependent on plasma levels of pyrophosphate. Kidney Int 85:1351-6|
|Lomashvili, Koba A; Wang, Xiaonan; O'Neill, W Charles (2014) Role of local versus systemic vitamin D receptors in vascular calcification. Arterioscler Thromb Vasc Biol 34:146-51|