Although many of the genetic changes
Although many of the genetic changes remain to be elucidated, there is evidence to support a difference in incidence and rate of rupture of cerebral aneurysms between men and women, and between pre- and postmenopausal women, suggesting that aneurysm formation may be affected by hormonal changes.18, 19, 20, 21 Specifically, estrogen and its interactions with estrogen receptors have been shown to be associated with regulation of arterial 412 2 sale matrix, mediation of inflammation, and regulation of proteolytic and apoptotic pathways.22, 23, 24, 25 Treatment with exogenous estrogen in ovariectomized or oophorectomized rodents resulted in protection against the development and rupture of cerebral aneurysms, suggesting that the estrogen signaling pathway plays an integral role in the pathophysiology of cerebral aneurysms.26, 27 Earlier menopausal age is also associated with the development of cerebral aneurysms in women, whereas the use of hormone replacement therapy is protective against the formation of aneurysms, further strengthening this association between estrogens and cerebral aneurysm formation.28, 29 In this study, we sought to identify genes in the estrogen signaling pathway that are associated with the formation of cerebral aneurysm via a meta-analysis.
Results A total of 98 genes were found to be associated with the estrogen transcription pathway, of which 94 were present in all 6 GEO databases. Nine individual samples in total were removed from 3 series (GSE26969, GSE6551, and GSE75436) for not meeting criteria for quality control with SD from the tissue-specific median of >0.3. The final analysis is comprised of 87 samples (49 aneurysmal cases and 38 control cases). A random-effects model was used to evaluate 94 genes associated with the estrogen receptor signaling pathway from the 6 GEO databases. A heatmap of the gene expression of the 94 genes is shown in Figure 2. After multiple-testing adjustment, 4 genes were identified to be statistically significant (Table 2). Of the 4 genes identified, PIK3R1 (fold change [FC] = 0.41, FDR = 6.1 × 10–5) and ADCY9 (FC = 0.55, FDR = 2.3 × 10–4) were found to be downregulated and HBEGF (FC = 1.4, FDR = 4.9 × 10–4) and ADCY7 (FC = 2.11, FDR = 6.0 × 10–3) were found to be upregulated. Figure 3 demonstrates the location of the 4 significant genes in the estrogen receptor signaling pathway in the Kyoto Encyclopedia of Genes and Genomes database. To further analyze the effects of estrogen receptor pathway in different sexes, a subgroup analysis was performed for each sex using the GEO databases (GSE15629 and GSE54083) with available information on sex (Table 3). PIK3R1 was found to be downregulated in both men (FC = 0.46, FDR = 6.3 × 10–5) and women (FC = 0.46, FDR = 2.3 × 10–4). PIK3R1 was the only gene found to be significant in men after multiple testing adjustment. In women, 3 additional genes (JUN, ADCY5, and MMP9) were also found to be differentially expressed in cerebral aneurysm tissue.
Discussion Estrogen's effect on the regulation of the cerebrovascular system and its association with various vascular diseases, including stroke, trauma, and dementia, has been demonstrated22, 37, 38, 39, 40 and thought to be related to the reduction of inflammation and maintenance of vessel wall integrity. In particular, estrogen has been postulated to play a significant role in the development of intracranial aneurysms. The nuclear estrogen receptor alpha and estrogen receptor beta, and a cytoplasmic G-coupled protein receptor, have been identified in human cerebral vascular endothelial cells and demonstrated in in situ studies to interact with estradiol. Specifically, the endogenous estrogen, estradiol, binds to both estrogen receptor alpha and estrogen receptor beta in the cell nucleus to mediate long-term alteration of downstream gene expression. More recently, G-coupled protein receptor has also been shown to mediate estrogenic responses in the regulation of vasorelaxation and the inhibition of smooth muscle proliferation.