Vascular calcification, commonly known as """"""""hardening of the arteries"""""""", is a major risk factor and independent predictor of cardiovascular mortality in the general population as well as high-risk diabetic and chronic kidney disease patients. Vascular calcification is highly correlated with atherosclerotic plaque burden, and the degree of calcification predicts increased risk of adverse clinical events and death. In addition, vascular calcification is associated with hypertension, cardiac valve disease, artificial heart valve calcification, and other forms of arteriosclerosis. It leads to cardiac valve stenosis, increased pulse pressure, hypertension and may contribute to plaque rupture, all of which can lead to heart failure. Importantly, there are currently no drugs to treat vascular calcification, and drugs that are commonly used to treat cardiovascular disease, such as statins, are not effective against vascular calcification. Thus, there is a great need for a better understanding of the origins of cells that participate in vascular calcification, as well as the mechanisms that regulate these cells such that appropriate preventative and therapeutic strategies can be developed to treat this debilitating pathology. In the past funding period, we identified a critical role for vascular smooth muscle cell (SMC) lineage reprogramming to osteochondrogenic precursors in vascular calcification. Using genetic fate mapping strategies in mouse models of arterial intimal (LDLR-/- and ApoE-/- mice) and medial calcification (MGP-/- mice), SMCs were found to be a major source of osteochondrogenic precursors and chondrocytes in the calcified vasculature. In both intimal and medial calcification models, the lineage reprogramming of SMCs towards an osteochondrogenic was preceded by de novo expression of Runx2 (also known as Cbfa1), a transcription factor required for normal bone and cartilage development. Furthermore, Erk1/2 signaling was required for SMC osteochondrocytic phenotype change in vitro. Based on these data, our overall hypothesis is that SMCs undergo lineage reprogramming in response to disease-specific, procalcific cues that convergeon a common downstream mediator, Runx2 (Figure 1) via the activation of Erk1/2. Runx2 phosphorylation by Erk1/2 leads to turn on of osteochondrogenic gene expression, and turn off of smooth muscle gene expression thereby reprogramming the smooth muscle cell towards an osteochondrogenic fate. In this proposal, we will definitively test this hypothesis by determining whether Runx2/Cbfa1 is required for vascular calcification under different disease settings and by further delineating the requirement and mechanisms of Erk signaling in Runx2- associated SMC lineage reprogramming and calcification.
Vascular calcification is prevalent in patients with diabetes, valve disease, chronic kidney disease and in the aged, and is a major independent predictor of cardiovascular morbidity and mortality. Currently, there are no drug therapies for vascular calcification. The longterm goal of our studies is to understand the origins of cells that participate in vascular calcification and the mechanisms regulating their mineralizing functions, such that appropriate preventative and therapeutic strategies can be developed.
|Paloian, Neil J; Leaf, Elizabeth M; Giachelli, Cecilia M (2016) Osteopontin protects against high phosphate-induced nephrocalcinosis and vascular calcification. Kidney Int 89:1027-36|
|Yamada, Shunsuke; Giachelli, Cecilia M (2016) Vascular calcification in CKD-MBD: Roles for phosphate, FGF23, and Klotho. Bone :|
|Wallingford, Mary C; Gammill, Hilary S; Giachelli, Cecilia M (2016) Slc20a2 deficiency results in fetal growth restriction and placental calcification associated with thickened basement membranes and novel CD13 and lamininÎ±1 expressing cells. Reprod Biol 16:13-26|
|Lin, Mu-En; Chen, Theodore; Leaf, Elizabeth M et al. (2015) Runx2 Expression in Smooth Muscle Cells Is Required for Arterial Medial Calcification in Mice. Am J Pathol 185:1958-69|
|Wallingford, Mary C; Giachelli, Cecilia M (2014) Loss of PiT-1 results in abnormal endocytosis in the yolk sac visceral endoderm. Mech Dev 133:189-202|
|Paloian, Neil J; Giachelli, Cecilia M (2014) A current understanding of vascular calcification in CKD. Am J Physiol Renal Physiol 307:F891-900|
|Yutzey, Katherine E; Demer, Linda L; Body, Simon C et al. (2014) Calcific aortic valve disease: a consensus summary from the Alliance of Investigators on Calcific Aortic Valve Disease. Arterioscler Thromb Vasc Biol 34:2387-93|
|Lau, Wei Ling; Linnes, Michael; Chu, Emily Y et al. (2013) High phosphate feeding promotes mineral and bone abnormalities in mice with chronic kidney disease. Nephrol Dial Transplant 28:62-9|
|Wu, Meiting; Rementer, Cameron; Giachelli, Cecilia M (2013) Vascular calcification: an update on mechanisms and challenges in treatment. Calcif Tissue Int 93:365-73|
|Crouthamel, Matthew H; Lau, Wei Ling; Leaf, Elizabeth M et al. (2013) Sodium-dependent phosphate cotransporters and phosphate-induced calcification of vascular smooth muscle cells: redundant roles for PiT-1 and PiT-2. Arterioscler Thromb Vasc Biol 33:2625-32|
Showing the most recent 10 out of 29 publications