Vascular calcification and aortic fibrosis: a bifunctional role for osteopontin in diabetic arteriosclerosis.

OBJECTIVE: Calcification and fibrosis reduce vascular compliance in arteriosclerosis. To better understand the role of osteopontin (OPN), a multifunctional protein upregulated in diabetic arteries, we evaluated contributions of OPN in male low-density lipoprotein receptor (LDLR)-/- mice fed a high-fat diet. METHODS AND RESULTS: OPN had no impact on high-fat diet-induced hyperglycemia, dyslipidemia, or body composition. However, OPN-/-;LDLR-/- mice exhibited an altered time-course of aortic calcium accrual-reduced during initiation but increased with progression-versus OPN+/+;LDLR-/- controls. Collagen accumulation, chondroid metaplasia, and mural thickness were increased in aortas of OPN-/-;LDLR-/- mice. Aortic compliance was concomitantly reduced. Vascular reexpression of OPN (SM22-OPN transgene) reduced aortic Col2A1 and medial chondroid metaplasia but did not affect atherosclerotic calcification, Col1A1 expression, collagen accumulation, or arterial stiffness. Dosing with the proinflammatory OPN fragment SVVYGLR upregulated aortic Wnt and osteogenic gene expression, increased aortic ß-catenin, and restored early-phase aortic calcification in OPN-/-;LDLR-/- mice. CONCLUSIONS: OPN exerts stage-specific roles in arteriosclerosis in LDLR-/- mice. Actions phenocopied by the OPN metabolite SVVYGLR promote osteogenic calcification processes with disease initiation. OPN limits vascular chondroid metaplasia, endochondral mineralization, and collagen accumulation with progression. Complete deficiency yields a net increase in arteriosclerotic disease, reducing aortic compliance and conduit vessel function in LDLR-/- mice.

Partial characterization and distribution of the chemokines CCL25 and CCL28 in the bovine system.

Chemokines have been shown to play a major role in the efficient accumulation and localization of leukocytes to tissues via interactions with their cognate receptors. The chemokine/chemokine receptor pairs CCL25/CCR9 and CCL28/CCR10 have been shown to play a vital role in the trafficking of antibody secreting cells to mucosal tissues. Although the importance of these chemokines in mediating effective immune responses is well described, the distribution of these molecules has not been previously characterized in the cow. In this report we describe the mRNA expression patterns of these chemokine/chemokine receptor pairs in the bovine system. Quantitative mRNA analysis shows that these molecules exhibit unique expression patterns and suggest that these chemokines play a major role in the accumulation of receptor bearing cells to specific mucosal tissues.

Activation of vascular smooth muscle parathyroid hormone receptor inhibits Wnt/beta-catenin signaling and aortic fibrosis in diabetic arteriosclerosis.

RATIONALE: Vascular fibrosis and calcification contribute to diabetic arteriosclerosis, impairing Windkessel physiology necessary for distal tissue perfusion. Wnt family members, upregulated in arteries by the low-grade inflammation of "diabesity," stimulate type I collagen expression and osteogenic mineralization of mesenchymal progenitors via beta-catenin. Conversely, parathyroid hormone (PTH) inhibits aortic calcification in low-density lipoprotein receptor (LDLR)-deficient mice fed high fat diabetogenic diets (HFD). OBJECTIVE: We sought to determine the impact of vascular PTH receptor (PTH1R) activity on arteriosclerotic Wnt/beta-catenin signaling in vitro and in vivo. We generated SM-caPTH1R transgenic mice, a model in which the constitutively active PTH1R variant H223R (caPTH1R) is expressed only in the vasculature. METHODS AND RESULTS: The caPTH1R inhibited Wnt/beta-catenin signaling, collagen production, and vascular smooth muscle cell proliferation and calcification in vitro. Transgenic SM-caPTH1R;LDLR(+/-) mice fed HFD develop diabesity, with no improvements in fasting serum glucose, cholesterol, weight, body composition, or bone mass versus LDLR(+/-) siblings. SM-caPTH1R downregulated aortic Col1A1, Runx2, and Nox1 expression without altering TNF, Msx2, Wnt7a/b, or Nox4. The SM-caPTH1R transgene decreased aortic beta-catenin protein accumulation and signaling in diabetic LDLR(+/-) mice. Levels of aortic superoxide (a precursor of peroxide that activates pro-matrix metalloproteinase 9 and osteogenic signaling in vascular smooth muscle cells) were suppressed by the SM-caPTH1R transgene. Aortic calcification, collagen accumulation, and wall thickness were concomitantly reduced, enhancing vessel distensibility. CONCLUSIONS: Cell-autonomous vascular smooth muscle cell PTH1R activity inhibits arteriosclerotic Wnt/beta-catenin signaling and reduces vascular oxidative stress, thus limiting aortic type I collagen and calcium accrual in diabetic LDLR-deficient mice.

An indispensable role for the chemokine receptor CCR10 in IgA antibody-secreting cell accumulation.

The differential expression of chemokines and chemokine receptors, by tissues and leukocytes, respectively, contributes to the specific accumulation of leukocyte subsets to different tissues. CCR10/CCL28 interactions are thought to contribute to the accumulation of IgA Ab-secreting cells (ASC) to mucosal surfaces, such as the gastrointestinal tract and the lactating mammary gland. Although the role of CCL28 in lymphocyte homing is well established, direct in vivo evidence for CCR10 involvement in this process has not been previously shown. In this study, we describe the generation of a CCR10-deficient mouse model. Using this model, we demonstrate that CCR10 is critical for efficient localization and accumulation of IgA ASC to the lactating mammary gland. Surprisingly, IgA ASC accumulation to the gastrointestinal tract is minimally impacted in CCR10-deficient mice. These results provide the first direct evidence of CCR10 involvement in lymphocyte homing and accumulation in vivo, and demonstrate that reliance on CCR10-mediated recruitment of IgA ASC varies dramatically within mucosal tissues.