title: Transgenic Overexpression of Tissue-Nonspecific Alkaline Phosphatase (TNAP) in Vascular Endothelium Results in Generalized Arterial Calcification.
abstract: BACKGROUND
  Ectopic vascular calcification is a common condition associated with aging, atherosclerosis, diabetes, and/or chronic kidney disease. Smooth muscle cells are the best characterized source of osteogenic progenitors in the vasculature; however, recent studies suggest that cells of endothelial origin can also promote calcification. To test this, we sought to increase the osteogenic potential of endothelial cells by overexpressing tissue-nonspecific alkaline phosphatase (TNAP), a key enzyme that regulates biomineralization, and to determine the pathophysiological effect of endothelial TNAP on vascular calcification and cardiovascular function.
  
  
  RESULTS
  We demonstrated previously that mice transgenic for ALPL (gene encoding human TNAP) develop severe arterial medial calcification and reduced viability when TNAP is overexpressed in smooth muscle cells. In this study, we expressed the ALPL transgene in endothelial cells following endothelial-specific Tie2-Cre recombination. Mice with endothelial TNAP overexpression survived well into adulthood and displayed generalized arterial calcification. Genes associated with osteochondrogenesis (Runx2, Bglap, Spp1, Opg, and Col2a1) were upregulated in the aortas of endothelial TNAP animals compared with controls. Lesions in coronary arteries of endothelial TNAP mice showed immunoreactivity to Runx2, osteocalcin, osteopontin, and collagen II as well as increased deposition of sialoproteins revealed by lectin staining. By 23 weeks of age, endothelial TNAP mice developed elevated blood pressure and compensatory left ventricular hypertrophy with preserved ejection fraction.
  
  
  CONCLUSIONS
  This study presented a novel genetic model demonstrating the osteogenic potential of TNAP-positive endothelial cells in promoting pathophysiological vascular calcification.
authors.affiliation: Children's Health Research Center, Sanford Research, Sioux Falls, SD (A.Y.S., M.S., I.R., O.V.S.) Department of Pediatrics, Sanford School of Medicine, University of South Dakota, Sioux Falls, SD (A.Y.S.).
authors.forename: Alexei Y
authors.initials: AY
authors.lastname: Savinov
authors.affiliation: Children's Health Research Center, Sanford Research, Sioux Falls, SD (A.Y.S., M.S., I.R., O.V.S.) Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, SD (M.S.).
authors.forename: Maryam
authors.initials: M
authors.lastname: Salehi
authors.affiliation: Sanford Children's Health Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA (M.C.Y., J.L.M.).
authors.forename: Manisha C
authors.initials: MC
authors.lastname: Yadav
authors.affiliation: Children's Health Research Center, Sanford Research, Sioux Falls, SD (A.Y.S., M.S., I.R., O.V.S.).
authors.forename: Ilian
authors.initials: I
authors.lastname: Radichev
authors.affiliation: Sanford Children's Health Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA (M.C.Y., J.L.M.).
authors.forename: José Luis
authors.initials: JL
authors.lastname: Millán
authors.affiliation: Children's Health Research Center, Sanford Research, Sioux Falls, SD (A.Y.S., M.S., I.R., O.V.S.).
authors.forename: Olga V
authors.initials: OV
authors.lastname: Savinova
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism*; D000818:Animals; D002114:Calcinosis / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D005260:Female; D015870:Gene Expression; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D058729:Peripheral Arterial Disease / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction
chemical_list: C510878:ALPL protein, mouse; D000469:Alkaline Phosphatase
keywords: arteriosclerosis; cardiovascular diseases; endothelium; enzymes; lesion