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Reversal of flow direction enhances endothelial cell arteriogenic signaling (670.9)
Author(s) -
Heuslein Joshua,
Meisner Joshua,
Price Richard
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.670.9
Subject(s) - arteriogenesis , klf2 , umbilical vein , microbiology and biotechnology , shear stress , endothelium , medicine , biology , anatomy , angiogenesis , gene expression , gene , in vitro , materials science , biochemistry , composite material
The key initiating stimulus for arteriogenesis in the presence of an arterial occlusion is altered shear stress along collateral arterial pathways that bypass the occlusion. Femoral artery occlusion in the mouse leads to increased flow across all collateral arteries with some collateral segments also experiencing a reversal of flow direction. We have recently shown that these “flow reversed” segments exhibited a 4‐fold increase in leukocyte recruitment and demonstrated enhanced arteriogenesis in the gracilis collateral network. To test if endothelial cell sensitivity to the flow‐direction change was a key element of the enhanced arteriogenesis, we applied the measured the in vivo hemodynamic changes of the gracilis collateral network to cultured human umbilical vein endothelial cells (HUVECs) and performed genome‐wide transcriptional profiling and pathways analysis. Endothelial cells demonstrated a 10‐fold greater number of genes sensitive to the additional flow‐reversal stimulus, as well as a broad amplification of the gene expression patterns of cells only exposed to an increase in shear stress magnitude. Further, the addition of flow‐reversal activated many of the signaling pathways known to be key mediators of collateral growth (e.g. p38 MAPK, VEGF, HGF, PKC, and NF‐κB) when compared to steady shear stress control. These were not activated with increased shear stress alone. Microarray results were further validated by RT‐PCR of a subset of known pro‐arteriogenic genes (KLF2, eNOS, and ICAM‐1) which demonstrated an increased expression with flow reversal. These results are consistent with an increase in shear stress alone as insufficient to fully achieve the maximal activation of the arteriogenic pathway. Incorporation of directional reversal may, therefore, provide a more physiological stimulus for interrogating the central pathways that drive arteriogenesis thus leading toward novel, more effective therapeutic options. Grant Funding Source : Supported by NIH 5R01HL074082, NIH1R21HL098632, AHA 09PRE2060385 AHA 10GRNT3490001, NSF GRFP DGE‐131