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Dysregulated selectin expression and monocyte recruitment during ischemia-related vascular remodeling in diabetes mellitus.

ABSTRACT: Diabetes mellitus (DM) is associated with impaired ischemia-related vascular remodeling and also dysregulation of the inflammatory response. We sought to determine whether impaired selectin-mediated monocyte recruitment in ischemic tissues contributes to blunted ischemia-mediated angiogenesis in DM.Contrast-enhanced ultrasound perfusion imaging and molecular imaging of endothelial P-selectin expression in the proximal hindlimb were performed at 1, 3, and 21 days after arterial ligation in wild-type and db/db mice. Ligation reduced muscle blood flow to ?0.05 mL/minute per gram in both strains. Significant recovery of flow occurred only in wild-type mice (60%-65% of baseline flow). On molecular imaging, baseline P-selectin signal was 4-fold higher in db/db compared with wild-type mice (P<0.01) but increased minimally at day 1 after ischemia, whereas signal increased approximately 10-fold in wild-type mice (P<0.01). Immunohistology of the hindlimb skeletal muscle demonstrated severely reduced monocyte recruitment in db/db mice compared with wild-type mice. Local treatment with monocyte chemotactic protein-1 corrected the deficits in postischemic P-selectin expression and monocyte recruitment in db/db mice and led to greater recovery in blood flow.In DM, there is dysregulation of the selectin response to limb ischemia, which leads to impaired monocyte recruitment, which may be mechanistically related to reduced vascular remodeling in limb ischemia.

SUBMITTER: Carr CL

PROVIDER: S-EPMC3202967 | biostudies-other | 2011 Nov

REPOSITORIES: biostudies-other

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Dysregulated selectin expression and monocyte recruitment during ischemia-related vascular remodeling in diabetes mellitus.

Carr Chad L CL Qi Yue Y Davidson Brian B Chadderdon Scott S Jayaweera Ananda R AR Belcik J Todd JT Benner Cameron C Xie Aris A Lindner Jonathan R JR

Arteriosclerosis, thrombosis, and vascular biology 20111101 11

<h4>Objective</h4>Diabetes mellitus (DM) is associated with impaired ischemia-related vascular remodeling and also dysregulation of the inflammatory response. We sought to determine whether impaired selectin-mediated monocyte recruitment in ischemic tissues contributes to blunted ischemia-mediated angiogenesis in DM.<h4>Methods and results</h4>Contrast-enhanced ultrasound perfusion imaging and molecular imaging of endothelial P-selectin expression in the proximal hindlimb were performed at 1, 3, ...[more]

PMID: 21885854

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Project description:OBJECTIVE:NKX2-5 is a homeobox transcription factor that is required for the formation of the heart and vessels during development, with significant postnatal down-regulation and reactivation in disease states, characterized by vascular remodeling. The purpose of this study was to investigate mechanisms that activate NKX2-5 expression in diseased vessels, such as systemic sclerosis (scleroderma; SSc)-associated pulmonary hypertension (PH), and to identify genetic variability that potentially underlies susceptibility to specific vascular complications. METHODS:We explored NKX2-5 expression in biopsy samples from patients with SSc-associated PH and in pulmonary artery smooth muscle cells (PASMCs) from patients with scleroderma. Disease-associated putative functional single-nucleotide polymorphisms (SNPs) at the NKX2-5 locus were cloned and studied in reporter gene assays. SNP function was further examined through protein-DNA binding assays, chromatin immunoprecipitation assays, and RNA silencing analyses. RESULTS:Increased NKX2-5 expression in biopsy samples from patients with SSc-associated PH was localized to remodeled vessels and PASMCs. Meta-analysis of 2 independent scleroderma cohorts revealed an association of rs3131917 with scleroderma (P = 0.029). We demonstrated that disease-associated SNPs are located in a novel functional enhancer, which increases NKX2-5 transcriptional activity through the binding of GATA-6, c-Jun, and myocyte-specific enhancer factor 2C. We also characterized an activator/coactivator transcription-enhancer factor domain 1 (TEAD1)/Yes-associated protein 1 (YAP1) complex, which was bound at rs3095870, another functional SNP, with TEAD1 binding the risk allele and activating the transcription of NKX2-5. CONCLUSION:NKX2-5 is genetically associated with scleroderma, pulmonary hypertension, and fibrosis. Functional evidence revealed a regulatory mechanism that results in NKX2-5 transcriptional activation in PASMCs through the interaction of an upstream promoter and a novel downstream enhancer. This mechanism can act as a model for NKX2-5 activation in cardiovascular disease characterized by vascular remodeling.

Dataset Information

Dysregulated selectin expression and monocyte recruitment during ischemia-related vascular remodeling in diabetes mellitus.

Publications

Dysregulated selectin expression and monocyte recruitment during ischemia-related vascular remodeling in diabetes mellitus.

Similar Datasets

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