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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
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Srinivas, Pothur R
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University of Washington
Engineering (All Types)
Schools of Medicine
United States
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Yamada, Shunsuke; Leaf, Elizabeth M; Chia, Jia Jun et al. (2018) PiT-2, a type III sodium-dependent phosphate transporter, protects against vascular calcification in mice with chronic kidney disease fed a high-phosphate diet. Kidney Int 94:716-727
Yamada, Shunsuke; Wallingford, Mary C; Borgeia, Suhaib et al. (2018) Loss of PiT-2 results in abnormal bone development and decreased bone mineral density and length in mice. Biochem Biophys Res Commun 495:553-559
Scatena, Marta; Jackson, Melissa F; Speer, Mei Y et al. (2018) Increased Calcific Aortic Valve Disease in response to a diabetogenic, procalcific diet in the LDLr-/-ApoB100/100 mouse model. Cardiovasc Pathol 34:28-37
Jackson, Melissa F; Scatena, Marta; Giachelli, Cecilia M (2017) Osteoclast precursors do not express CD68: results from CD68 promoter-driven RANK transgenic mice. FEBS Lett 591:728-736
Yamada, Shunsuke; Giachelli, Cecilia M (2017) Vascular calcification in CKD-MBD: Roles for phosphate, FGF23, and Klotho. Bone 100:87-93
Giachelli, Cecilia M; Speer, Mei Y (2017) Noncanonical Wnts at the Cusp of Fibrocalcific Signaling Processes in Human Calcific Aortic Valve Disease. Arterioscler Thromb Vasc Biol 37:387-388
Wallingford, Mary Catherine; Chia, Jia Jun; Leaf, Elizabeth M et al. (2017) SLC20A2 Deficiency in Mice Leads to Elevated Phosphate Levels in Cerbrospinal Fluid and Glymphatic Pathway-Associated Arteriolar Calcification, and Recapitulates Human Idiopathic Basal Ganglia Calcification. Brain Pathol 27:64-76
Paloian, Neil J; Leaf, Elizabeth M; Giachelli, Cecilia M (2016) Osteopontin protects against high phosphate-induced nephrocalcinosis and vascular calcification. Kidney Int 89:1027-1036
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 laminin?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

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