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Early and sustained medial cell activation after aortocaval fistula creation in mice
Raul J Guzman1, Andrew Krystkowiak, Christopher K Zarins
1Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA. raul.guzman@vanderbilt.edu
Background:
The response of endothelial cells to altered flow conditions has been studied extensively. However, the indirect effects of shear stress on medial smooth muscle cells (SMCs) have been less well characterized and a murine model of high shear stress has not been available.
Materials And Methods:
The hemodynamic changes that occur in a mouse aorta proximal to an aortocaval fistula (ACF) were characterized by measuring blood flow, aortic diameter, and calculating wall shear stress. This model was next used to evaluate cellular activation by assessing beta-galactosidase expression in fos-lacZ transgenic mice. Aortic specimens were examined by a chemiluminescent beta-galactosidase assay, cross-sectional histology, and Hautchen prep en face histology.
Results:
Immediately after ACF construction, aortic diameter remained unchanged and wall shear stress increased 2.6-fold (49.57 +/- 5.89 to 134.93 +/- 15.69 dyn/cm(2), P < 0.05). Flow-induced aortic enlargement occurred gradually (0.61 +/- 0.03 to 1.18 +/- 0.05 mm at 21 days, P < 0.5) such that by 21 days after ACF, wall shear stress had returned to baseline (56.97 +/- 8.62 dyn/cm(2), P = ns compared to control). Aortas from fos-lacZ mice demonstrated increased beta-gal activity at 6 h and up to 7 days after ACF (1.81 +/- 0.22 rlu/microg in controls vs 41.41 +/- 16.28 rlu/microg at 6 h and 15.17 +/- 1.1 rlu/microg at 7 days, P < 0.5) On histologic evaluation, there was a significant increase in medial SMC staining that was most prominent in cells near the intima (2 +/- 0.3% positive cells in controls vs 67 +/- 10% at 6 h and 11 +/- 7.6 at 7 days, P < 0.5). Endothelial cells, evaluated by en face methods, did not demonstrate significant amounts of beta-gal positivity at the times studied.
Conclusions:
These in vivo findings using a new high shear stress model suggest that early and sustained activation of medial SMCs is a critical component of flow-induced enlargement. Further evaluation of these events may provide important insights into the mechanisms of pathologic arterial remodeling.