Skip to Main Content
 

Global Search Box

 
 
 
 

Files

File List


case1266605413.pdf (1.34 MB)

ETD Abstract Container

Abstract Header

Extracellular Pyrophosphate Homeostasis and Regulation of Vascular Calcification in Vascular Smooth Muscle Cells

Prosdocimo, Domenick A.
http://rave.ohiolink.edu/etdc/view?acc_num=case1266605413

Abstract Details

2010, Doctor of Philosophy, Case Western Reserve University, Physiology and Biophysics.
Extracellular inorganic pyrophosphate (PPi) is a potent suppressor of physiological calcification in bone and pathological calcification in blood vessels. Extracellular PPi homeostasis is maintained by three plasma membrane proteins. Ecto-nucleotide pyrophosphatase / phosphodiesterase-1 (ENPP1) and progressive ankylosis disease susceptibility gene product (ANK) serve to generate extracellular PPi via extracellular and intracellular mechanisms, respectively, involving ATP hydrolysis while tissue nonselective alkaline phosphatase (TNAP) acts to hydrolyze the locally generated PPi. The loss of circulating or local levels of PPi is linked both in vivo and in vitro to vascular calcification involving resident vascular smooth muscle cells (VSMC) within the medial layer of large capacitance arteries such as the aorta. However, the precise mechanism(s) by which VSMC regulate extracellular PPi homeostasis under non- and pro-calcifying conditions remains unknown. This thesis describes an autocrine mechanism of extracellular PPi generation in cultured rat aortic VSMC that involves both ATP release coupled to ENPP1 and the efflux of intracellular PPi mediated or regulated by the ANK plasma membrane protein. We extend these initial findings and report that two signals reported to potentiate VSMC calcification, increased cAMP signaling and hyperphosphatemia, act synergistically to induce a calcification of these VSMC that is correlated with the progressive reduction in their ability to accumulate extracellular PPi. Attenuated PPi accumulation was mediated in part by a cAMP-dependent decrease in ANK expression, a cAMP-dependent increase in expression of TNAP, and a cAMP / phosphate (Pi) induced decrease in the ATP release pathway(s) that supports ENPP1 activity. Further, preliminary studies support a role for tumor necrosis factor-α (TNFα), a pleiotropic pro-inflammatory cytokine known to induce vascular calcification, in potentiating Pi-induced VSMC calcification by a mechanism involving reduced extracellular PPi generation which is correlated to a reduction in ANK mRNA levels. These observations support a model wherein extracellular PPi generation mediated by both ANK- and ATP release-dependent mechanisms serves as a critical regulator of VSMC calcification. Future experiments identifying the mechanism by which ATP is released and the signaling pathways which regulate the expression of these PPi homeostatic proteins would provide valuable insight into the molecular mechanism(s) of VSMC calcification.
George R. Dubyak, PhD (Advisor)
Thomas Nosek, PhD (Committee Chair)
Margaret Chandler, PhD (Committee Member)
Andrea Romani, PhD (Committee Member)
Steven Fisher, MD (Committee Member)
192 p.
Anatomy and Physiology; Biomedical Research
ATP release; vascular calcification; pyrophosphate; ENPP1; ANK; TNAP

Recommended Citations

Citations

  • Prosdocimo, D. A. (2010). Extracellular Pyrophosphate Homeostasis and Regulation of Vascular Calcification in Vascular Smooth Muscle Cells [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1266605413

    APA Style (7th edition)

  • Prosdocimo, Domenick. Extracellular Pyrophosphate Homeostasis and Regulation of Vascular Calcification in Vascular Smooth Muscle Cells. 2010. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1266605413.

    MLA Style (8th edition)

  • Prosdocimo, Domenick. "Extracellular Pyrophosphate Homeostasis and Regulation of Vascular Calcification in Vascular Smooth Muscle Cells." Doctoral dissertation, Case Western Reserve University, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=case1266605413

    Chicago Manual of Style (17th edition)

case1266605413
937
© 2010, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.