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Adaptive response of vascular endothelial cells to an acute increase in shear stress magnitude.

ABSTRACT: The adaptation of vascular endothelial cells to shear stress alteration induced by global hemodynamic changes, such as those accompanying exercise or digestion, is an essential component of normal endothelial physiology in vivo. An understanding of the transient regulation of endothelial phenotype during adaptation to changes in mural shear will advance our understanding of endothelial biology and may yield new insights into the mechanism of atherogenesis. In this study, we characterized the adaptive response of arterial endothelial cells to an acute increase in shear stress magnitude in well-defined in vitro settings. Porcine endothelial cells were preconditioned by a basal level shear stress of 15 ± 15 dyn/cm(2) at 1 Hz for 24 h, after which an acute increase in shear stress to 30 ± 15 dyn/cm(2) was applied. Endothelial permeability nearly doubled after 40-min exposure to the elevated shear stress and then decreased gradually. Transcriptomics studies using microarray techniques identified 86 genes that were sensitive to the elevated shear. The acute increase in shear stress promoted the expression of a group of anti-inflammatory and antioxidative genes. The adaptive response of the global gene expression profile is triphasic, consisting of an induction period, an early adaptive response (ca. 45 min) and a late remodeling response. Our results suggest that endothelial cells exhibit a specific phenotype during the adaptive response to changes in shear stress; this phenotype is different than that of fully adapted endothelial cells.

SUBMITTER: Zhang J

PROVIDER: S-EPMC3322739 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Adaptive response of vascular endothelial cells to an acute increase in shear stress magnitude.

Zhang Ji J Friedman Morton H MH

American journal of physiology. Heart and circulatory physiology 20111202 4

The adaptation of vascular endothelial cells to shear stress alteration induced by global hemodynamic changes, such as those accompanying exercise or digestion, is an essential component of normal endothelial physiology in vivo. An understanding of the transient regulation of endothelial phenotype during adaptation to changes in mural shear will advance our understanding of endothelial biology and may yield new insights into the mechanism of atherogenesis. In this study, we characterized the ada ...[more]

PMID: 22140046

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Project description:In vivo, vascular endothelial cells (VECs) are anchored to the underlying stroma through a specialization of the extracellular matrix, the basement membrane (BM) which provides a variety of substratum associated biophysical cues that have been shown to regulate fundamental VEC behaviors. VEC function and homeostasis are also influenced by hemodynamic cues applied to their apical surface. How the combination of these biophysical cues impacts fundamental VEC behavior remains poorly studied. In the present study, we investigated the impact of providing biophysical cues simultaneously to the basal and apical surfaces of human aortic endothelial cells (HAECs). Anisotropically ordered patterned surfaces of alternating ridges and grooves and isotropic holed surfaces of varying pitch (pitch = ridge or hole width + intervening groove or planar regions) were fabricated and seeded with HAECs. The cells were then subjected to a steady shear stress of 20 dyne/cm(2) applied either parallel or perpendicular to the direction of the ridge/groove topography. HAECs subjected to flow parallel to the ridge/groove topography exhibited protagonistic effects of the two stimuli on cellular orientation and elongation. In contrast, flow perpendicular to the substrate topography resulted in largely antagonistic effects. Interestingly, the behavior depended on the shape and size of the topographic features. HAECs exhibited a response that was less influenced by the substratum and primarily driven by flow on isotropically ordered holed surfaces of identical pitch to the anistropically ordered surfaces of alternating ridges and grooves. Simultaneous presentation of biophysical cues to the basal and apical aspects of cells also influenced nuclear orientation and elongation; however, the extent of nuclear realignment was more modest in comparison to cellular realignment regardless of the surface order of topographic features. Flow-induced HAEC migration was also influenced by the ridge/groove surface topographic features with significantly altered migration direction and increased migration tortuosity when flow was oriented perpendicular to the topography; this effect was also pitch-dependent. The present findings provide valuable insight into the interaction of biologically relevant apical and basal biophysical cues in regulating cellular behavior and promise to inform improved prosthetic design.

Project description:Objective: The vulnerability of atherosclerotic plaques is among the leading cause of ischemic stroke. High wall shear stress (WSS) promotes the instability of atherosclerotic plaques by directly imparting mechanical stimuli, but the specific mechanisms remain unclear. We speculate that modulation of mechanosensitive genes may play a vital role in accelerating the development of plaques. The purpose of this study was to find mechanosensitive genes in vascular endothelial cells (ECs) through combining microarray data with bioinformatics technology and further explore the underlying dynamics-related mechanisms that cause the progression and destabilization of atherosclerotic plaques. Methods: Microarray data sets for human vascular ECs under high and normal WSS were retrieved from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified through the R language. The performance of enrichment analysis and protein-protein interaction (PPI) network presented the biological function and signaling pathways of the DEGs. Hub genes were identified based on the PPI network and validated by GEO data sets. Predicted transcription factor (TF) genes and miRNAs interaction with potential mechanosensitive genes were identified by NetworkAnalyst. Results: A total of 260 DEGs, 121 upregulated and 139 downregulated genes, were screened between high and normal WSS from GSE23289. A total of 10 hub genes and four cluster modules were filtered out based on the PPI network. The enrichment analysis showed that the biological functions of the hub genes were mainly involved in responses to unfolded protein and topologically incorrect protein, and t to endoplasmic reticulum stress. The significant pathways associated with the hub genes were those of protein processing in the endoplasmic reticulum, antigen processing, and presentation. Three out of the 10 hub genes, namely, activated transcription factor 3 (ATF3), heat shock protein family A (Hsp70) member 6 (HSPA6), and dual specificity phosphatase 1 (DUSP1, also known as CL100, HVH1, MKP-1, PTPN10), were verified in GSE13712. The expression of DUSP1 was higher in the senescent cell under high WSS than that of the young cell. The TF-miRNA-mechanosensitive gene coregulatory network was constructed. Conclusion: In this work, we identified three hub genes, ATF3, HSPA6, and DUSP1, as the potential mechanosensitive genes in the human blood vessels. DUSP1 was confirmed to be associated with the senescence of vascular ECs. Therefore, these three mechanosensitive genes may have emerged as potential novel targets for the prediction and prevention of ischemic stroke. Furthermore, the TF-miRNA-mechanosensitive genes coregulatory network reveals an underlying regulatory mechanism and the pathways to control disease progression.

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Adaptive response of vascular endothelial cells to an acute increase in shear stress magnitude.

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Adaptive response of vascular endothelial cells to an acute increase in shear stress magnitude.

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