Effects And Underlying Mechnisms Of Altered Flow Shear Stress On Carotid Remodeling In Rat

Physiological flow shear stress plays a central role in anti-thrombus, maintaining barrier function and homestasis of blood vessel. The alterated flow shear stress would induce vessel remodeling, which was the common pathological foundation of vascular diseases such as atherosclerosis, hypertension and restenosis. Therefore, it is very important to eluciate the underlying mechanisms of the vascular remodeling induced by flow shear stress alterations for the prevention, diagnosis and treatment of cardiovascular diseases.In present study, the ligation of partial distal branches of the left common carotid (LCA) was performed, which resulted in different changes of flow shear stress in both carotids of the same rat. The sham-operation animals without arterial ligation were as a control group. The effects of shear stress alteration on remodeling of carotid arteries and underlying mechanisms were inspected. The morphometry, histology, and ultrastructures of the vessels were examined by both light microscopy and transmission electron microscopy. The changes of vascular opening angle at zero-stress state were detected. Apoptotic cells of the vascular wall were examined by TdT-mediated dUTP-biotin nick end labeling (TUNNEL) staining. The vascular internal elastic lamina (IEL) was insighted with horseradish peroxidase (HRP), a large molecular tracer, by laser confocal scanning microscopy. The expressions of calponin, fibronectin, p-Akt and p21 in the vascular wall were examined by immunohistochemistry and Western blotting. The activity of matrix metalloproteinases (MMPs) in the vascular wall was revealed by gelatin zymography.Our results revealed that: (1) The ligation of partial distal branches of LCA induced low shear stress of LCA and high shear stress of the contralateral right carotid arteries (RCA). At 7th day of post-operation both the inner diameter and opening angle of LCA were decreased, while the ratio of wall thickness to inner diameter was increased. RCA did not show such changes. The apoptic and dedifferentiated vascular smooth muscle cells were increased due to changes of shear stress. The thickness of sub-endothelial layer was increased in LCA significantly. (2) Low shear stress induced the decrease of IEL fenestrae, which resulted in abnormal molecular accumulation in the interstitial space underlying IEL with augmented expression of fibronectin, significantly different from RCA. (3) Changes of shear stress increased the MMPs activities and p-Akt expressions, while reduced expressions of p21 and calponin in vessels, which was reversed by Doxycycline, an inhibitor of MMPs.These results revealed that low shear stress induced structural changes of artery, especially IEL remodeling, and resulted in macromolecular accumulation in the arterial wall at more early in course of the alternation of shear stress. The alteration of shear stress induced MMPs activities in the vascular wall. Otherwise, the inhibitor of MMPs might benefit to the vascular remodeling induced by the alternation of shear stress.