CDKN2B Regulates TGFβ Signaling and Smooth Muscle Cell Investment of Hypoxic Neovessels.

Academic Article

Abstract

  • RATIONALE: Genetic variation at the chromosome 9p21 cardiovascular risk locus has been associated with peripheral artery disease, but its mechanism remains unknown. OBJECTIVE: To determine whether this association is secondary to an increase in atherosclerosis, or it is the result of a separate angiogenesis-related mechanism. METHODS AND RESULTS: Quantitative evaluation of human vascular samples revealed that carriers of the 9p21 risk allele possess a significantly higher burden of immature intraplaque microvessels than carriers of the ancestral allele, irrespective of lesion size or patient comorbidity. To determine whether aberrant angiogenesis also occurs under nonatherosclerotic conditions, we performed femoral artery ligation surgery in mice lacking the 9p21 candidate gene, Cdkn2b. These animals developed advanced hindlimb ischemia and digital autoamputation, secondary to a defect in the capacity of the Cdkn2b-deficient smooth muscle cell to support the developing neovessel. Microarray studies identified impaired transforming growth factor β (TGFβ) signaling in cultured cyclin-dependent kinase inhibitor 2B (CDKN2B)-deficient cells, as well as TGFβ1 upregulation in the vasculature of 9p21 risk allele carriers. Molecular signaling studies indicated that loss of CDKN2B impairs the expression of the inhibitory factor, SMAD-7, which promotes downstream TGFβ activation. Ultimately, this manifests in the upregulation of a poorly studied effector molecule, TGFβ1-induced-1, which is a TGFβ-rheostat known to have antagonistic effects on the endothelial cell and smooth muscle cell. Dual knockdown studies confirmed the reversibility of the proposed mechanism, in vitro. CONCLUSIONS: These results suggest that loss of CDKN2B may not only promote cardiovascular disease through the development of atherosclerosis but may also impair TGFβ signaling and hypoxic neovessel maturation.

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    Keywords

  • atherosclerosis, cyclin-dependent kinase inhibitor p15, genetic variation, pathologic angiogenesis, peripheral artery disease, smooth muscle cells, Animals, Atherosclerosis, Carotid Arteries, Cell Hypoxia, Cells, Cultured, Chromosomes, Human, Pair 9, Coronary Vessels, Cyclin-Dependent Kinase Inhibitor p15, Disease Models, Animal, Female, Genetic Predisposition to Disease, Hindlimb, Humans, Male, Mice, Inbred C57BL, Mice, Knockout, Muscle, Skeletal, Muscle, Smooth, Vascular, Myocytes, Smooth Muscle, Neovascularization, Pathologic, Neovascularization, Physiologic, Phenotype, RNA Interference, Signal Transduction, Smad7 Protein, Time Factors, Transfection, Transforming Growth Factor beta1

    • Digital Object Identifier (doi)

    Pubmed Id

  • 24694096

    • Author List

  • Nanda V; Downing KP; Ye J; Xiao S; Kojima Y; Spin JM; DiRenzo D; Nead KT; Connolly AJ; Dandona S

    • Start Page

  • 230

    • End Page

  • 240

    • Volume

  • 118

    • Issue

  • 2