Objective The pathogenesis of abdominal aortic aneurysm (AAA) formation includes inflammation, vascular smooth muscle cell apoptosis, extracellular matrix degradation, and oxidative stress. That ...multipotent stem cells have an important role in cardiovascular health and disease has been well established, but the role of stem cells in aortic structural deterioration is poorly defined. We sought to describe the presence of stem cells in human AAA tissue and also investigated the differentiation of stem cells within the aneurysmal aorta. Methods Infrarenal aortic wall specimens were collected from patients (n = 7) undergoing open AAA surgical repair. Nonaneurysmal infrarenal aortic control samples (n = 4) were collected at autopsies. Using immunohistochemistry, we compared the abundance of Stro1-positive (+ ), c-kit+ , and CD34+ cells in aortic tissue. Using double-immunofluorescence staining, we evaluated stem cell differentiation into smooth muscle cells (SM22), fibroblasts (FSP1), and macrophages (CD68). We then investigated the colocalization of CD68+ cells with the cellular marker of proliferation Ki67. Results The media and adventitia of infrarenal AAA samples both demonstrated a significantly greater number of c-kit+ and CD34+ cells compared with matched control nonaneurysmal aortic tissues; however, the abundance of Stro1+ cells was not significantly different between the groups. Using double-immunofluorescence staining, we identified that AAA stem cells express the macrophage marker CD68 but not the smooth muscle cell marker SM22 or the fibroblast marker FSP1. CD68+ cells within the aortic wall colocalized with the cellular marker of proliferation Ki67. Conclusions Stem cells are significantly elevated in infrarenal AAA tissue compared with matched control aortic tissue. Our data also demonstrate that AAA stem cells express macrophage surface antigens but not smooth muscle cell or fibroblast markers. Furthermore, CD68+ cells within the aortic wall colocalized with the cellular marker of proliferation Ki67. These finding suggest an inflammatory/immune role of stem cells during AAA pathogenesis and raise the possibility of localized replenishment therapy within the aneurysm wall.
Objective We sought to determine whether maternal/fetal single-nucleotide polymorphisms (SNPs) in candidate genes are associated with preterm prelabor rupture of membranes (pPROM). Study Design A ...case-control study was conducted in patients with pPROM (225 mothers and 155 fetuses) and 599 mothers and 628 fetuses with a normal pregnancy; 190 candidate genes and 775 SNPs were studied. Single locus/haplotype association analyses were performed; false discovery rate was used to correct for multiple testing (q* = 0.15). Results First, a SNP in tissue inhibitor of metalloproteinase 2 in mothers was significantly associated with pPROM (odds ratio, 2.12; 95% confidence interval, 1.47–3.07; P = .000068), and this association remained significant after correction for multiple comparisons. Second, haplotypes for Alpha 3 type IV collagen isoform precursor in the mother were associated with pPROM (global P = .003). Third, multilocus analysis identified a 3-locus model, which included maternal SNPs in collagen type I alpha 2, defensin alpha 5 gene, and endothelin 1. Conclusion DNA variants in a maternal gene involved in extracellular matrix metabolism doubled the risk of pPROM.
Objective The purpose of this study was to determine whether maternal/fetal single nucleotide polymorphisms (SNPs) in candidate genes are associated with spontaneous preterm labor/delivery. Study ...Design A genetic association study was conducted in 223 mothers and 179 fetuses (preterm labor with intact membranes who delivered <37 weeks of gestation preterm birth (PTB)), and 599 mothers and 628 fetuses (normal pregnancy); 190 candidate genes and 775 SNPs were studied. Single locus/haplotype association analyses were performed; the false discovery rate was used to correct for multiple testing. Results The strongest single locus associations with PTB were interleukin-6 receptor 1 (fetus; P = .000148) and tissue inhibitor of metalloproteinase 2 (mother; P = .000197), which remained significant after correction for multiple comparisons. Global haplotype analysis indicated an association between a fetal DNA variant in insulin-like growth factor F2 and maternal alpha 3 type IV collagen isoform 1 (global, P = .004 and .007, respectively). Conclusion An SNP involved in controlling fetal inflammation (interleukin-6 receptor 1) and DNA variants in maternal genes encoding for proteins involved in extracellular matrix metabolism approximately doubled the risk of PTB.
Objective The goal of this project was to identify genetic variants associated with abdominal aortic aneurysms (AAAs). Methods A genome wide association study was carried out using pooled DNA samples ...from 123 AAA cases and 112 controls matched for age, gender, and smoking history using Affymetrix 500K single nucleotide polymorphism (SNP) arrays (Affymetrix, Inc, Santa Clara, Calif). The difference in mean allele frequency between cases and controls was calculated for each SNP and used to identify candidate genomic regions. Association of candidate SNPs with AAA was confirmed by individual TaqMan genotype assays in a total of 2096 cases and controls that included an independent replication sample set. Results A genome wide association study of AAA cases and controls identified a candidate AAA-associated haplotype on chromosome 3p12.3. By individual genotype analysis, four SNPs in this region were significantly associated with AAA in cases and controls from the original study population. One SNP in this region (rs7635818) was genotyped in a total of 502 cases and 736 controls from the original study population ( P = .017) and 448 cases and 410 controls from an independent replication sample ( P = .013; combined P value = .0028; combined odds ratio OR = 1.33). An even stronger association with AAA was observed in a subset of smokers (391 cases, 241 controls, P = .00041, OR = 1.80), which represent the highest risk group for AAA. The AAA-associated haplotype is located ∼200 kbp upstream of the CNTN3 gene transcription start site. Conclusion This study identifies a region on chromosome 3 that is significantly associated with AAA in 2 distinct study populations.
Objective The objective of the study was to investigate changes in the expression of angiogenesis-related genes during the common terminal pathway of parturition including spontaneous labor at term, ...as well as preterm labor (PTL), induced by either bacteria or ovariectomy. Study Design Preterm pregnant mice (14.5 days of gestation) were treated with the following: (1) intrauterine injection of media; (2) intrauterine injection of heat-inactivated Escherichia coli ; (3) ovariectomy; and (4) sham operation. Tissues from mice at term (19.5 days of gestation) were collected at term not in labor, term in labor, and 12 hours postpartum. Angiogenesis-related gene expression levels were quantitated by the measurement of specific mRNAs in uterine tissue by RT-qPCR and analyzed by repeated-measures analysis of variance. Results The following results were found: (1) microarray analysis of the uterine transcriptome indicated an enrichment for the gene ontology category of angiogenesis in bacteria-induced PTL samples ( P ≤ .093); (2) several genes related to angiogenesis demonstrated significantly increased expression in samples in either term spontaneous labor or preterm labor; and (3) qRT-PCR measurements demonstrated that spontaneous term labor and preterm labor induced by either bacteria or ovariectomy all substantially increased the expression of multiple angiogenesis-related genes ( P ≤ .0003; Angpt2, Ctgf, Cyr61, Dscr1, Pgf, Serpine1, Thbs1, and Wisp 1). Conclusion Spontaneous labor at term, as well as pathologically induced preterm labor, all result in greatly increased expression of angiogenesis-related genes in the uterus.
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