Spatial heterogeneity of endothelial phenotypes correlates with side-specific vulnerability to calcification in normal porcine aortic valves
Spatial heterogeneity of endothelial phenotypes correlates with side-specific vulnerability to calcification in normal porcine aortic valves
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DOI：
10.1161/01.res.0000161998.92009.64
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发表时间：
2005-04-15
影响因子：
20.1
通讯作者：
Davies, PF
中科院分区：
文献类型：
--
作者：
Simmons, CA;Grant, GR;Davies, PF
钙化性主动脉瓣硬化包括炎症过程，并优先发生在内皮化瓣膜小叶的主动脉侧。尽管内皮被认为在局灶性血管硬化中起着关键作用，但瓣膜内皮表型对主动脉瓣硬化和侧特异性钙化易感性的贡献尚不清楚。利用RNA扩增和cDNA微阵列技术，我们鉴定出584个基因在正常成年猪主动脉瓣主动脉侧和心室侧的内皮原位表达上存在差异。这些不同的转录谱，代表了体内的稳定状态，确定了主动脉瓣相对两侧的内皮细胞的整体不同表型。在差异表达的基因中确定了几种被认为与瓣膜内稳态的内皮调节和主动脉侧对钙化的易感性相关的过度代表的生物学分类。值得注意的是，心血管钙化的多种抑制剂在瓣膜易发疾病的主动脉侧的内皮中表达明显减少，提示对钙化具有侧特异性。然而，也表达了共存的假定保护机制。具体来说，主动脉侧抗氧化基因表达的增强和促炎分子差异表达的缺乏可能保护正常瓣膜免受炎症和病变的发生。这些数据暗示内皮在调节瓣膜钙化，并提示瓣膜内皮表型的空间异质性可能有助于病变发展的局灶易感性。
Calcific aortic valve sclerosis involves inflammatory processes and occurs preferentially on the aortic side of endothelialized valve leaflets. Although the endothelium is recognized to play critical roles in focal vascular sclerosis, the contributions of valvular endothelial phenotypes to aortic valve sclerosis and side-specific susceptibility to calcification are poorly understood. Using RNA amplification and cDNA microarrays, we identified 584 genes as differentially expressed in situ by the endothelium on the aortic side versus ventricular side of normal adult pig aortic valves. These differential transcriptional profiles, representative of the steady state in vivo, identify globally distinct endothelial phenotypes on opposite sides of the aortic valve. Several over-represented biological classifications with putative relevance to endothelial regulation of valvular homeostasis and aortic-side vulnerability to calcification were identified among the differentially expressed genes. Of note, multiple inhibitors of cardiovascular calcification were significantly less expressed by endothelium on the disease-prone aortic side of the valve, suggesting side-specific permissiveness to calcification. However, coexisting putative protective mechanisms were also expressed. Specifically, enhanced antioxidative gene expression and the lack of differential expression of proinflammatory molecules on the aortic side may protect against inflammation and lesion initiation in the normal valve. These data implicate the endothelium in regulating valvular calcification and suggest that spatial heterogeneity of valvular endothelial phenotypes may contribute to the focal susceptibility for lesion development.