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Systems biology analysis of longitudinal functional response of endothelial cells to shear stress

  1. Shankar Subramaniama,b,d,g,h,1
  1. aBioinformatics and Systems Biology Graduate Program, University of California at San Diego, La Jolla, CA 92023;
  2. bDepartment of Bioengineering, University of California at San Diego, La Jolla, CA 92093;
  3. cSan Diego Supercomputer Center, University of California at San Diego, La Jolla, CA 92093;
  4. dInstitute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093;
  5. eDepartment of Medicine, University of California at San Diego, La Jolla, CA 92093;
  6. fDepartment of Diabetes Complications and Metabolism, Beckman Research Institute, City of Hope, CA 91010;
  7. gDepartment of Computer Science and Engineering, University of California, San Diego, La Jolla, CA 92093;
  8. hDepartment of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093
  1. Contributed by Shu Chien, August 25, 2017 (sent for review May 8, 2017; reviewed by Michael A. Gimbrone, Jie Liang, and Jason A. Papin)

Significance

Endothelial responses to shear stress modulate vascular homeostasis. This study offers a comprehensive temporal mechanistic model of shear stress response in cultured human vascular endothelial cells by presenting a systematic time-series RNA-sequencing dataset on endothelial cells exposed to pulsatile and oscillatory shears, consisting of 10 time points across 24 h. The experimental data were used for pathway analysis and construction of transcription factor-to-gene networks. The model highlights (i) dynamic regulation of several key shear-sensitive endothelial functions relevant to atheroprotective vs. atherogenic phenotype, (ii) how these functions may be causally interrelated, and (iii) how they are regulated by common upstream shear-responsive transcription factors. The results provide insights into the dynamics of functional evolution over time.

Abstract

Blood flow and vascular shear stress patterns play a significant role in inducing and modulating physiological responses of endothelial cells (ECs). Pulsatile shear (PS) is associated with an atheroprotective endothelial phenotype, while oscillatory shear (OS) is associated with an atheroprone endothelial phenotype. Although mechanisms of endothelial shear response have been extensively studied, most studies focus on characterization of single molecular pathways, mainly at fixed time points after stress application. Here, we carried out a longitudinal time-series study to measure the transcriptome after the application of PS and OS. We performed systems analyses of transcriptional data of cultured human vascular ECs to elucidate the dynamics of endothelial responses in several functional pathways such as cell cycle, oxidative stress, and inflammation. By combining the temporal data on differentially expressed transcription factors and their targets with existing knowledge on relevant functional pathways, we infer the causal relationships between disparate endothelial functions through common transcriptional regulation mechanisms. Our study presents a comprehensive temporally longitudinal experimental study and mechanistic model of shear stress response. By comparing the relative endothelial expressions of genes between OS and PS, we provide insights and an integrated perspective into EC function in response to differential shear. This study has significant implications for the pathogenesis of vascular diseases.

Footnotes

  • ?1To whom correspondence may be addressed. Email: jshyy{at}ucsd.edu, zhenchen{at}coh.org, shuchien{at}ucsd.edu, or shankar{at}ucsd.edu.
  • Author contributions: N.E.A., J.Y.-S.L., J.Y.-J.S., Z.C., S.C., and S.S. designed research; N.E.A., S.G., M.R.M., P.N., J.Y.-S.L., and Z.C. performed research; N.E.A., S.G., M.R.M., and Z.C. analyzed data; and N.E.A., J.Y.-J.S., Z.C., S.C., and S.S. wrote the paper.

  • Reviewers: M.A.G., Harvard Medical School; J.L., University of Illinois at Chicago; and J.A.P., University of Virginia.

  • The authors declare no conflict of interest.

  • Data deposition: The sequence data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, http://www.danielhellerman.com/geo (accession no. GSE103672).

  • This article contains supporting information online at www.danielhellerman.com/lookup/suppl/doi:10.1073/pnas.1707517114/-/DCSupplemental.

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