Enhanced External Counterpulsation Inhibits Intimal Hyperplasia by Modifying Shear Stress–Responsive Gene Expression in Hypercholesterolemic Pigs

Abstract

Background-Enhanced external counterpulsation (EECP) is a circulation assist device that may improve endothelial dysfunction by increasing shear stress. Chronic exposure of vascular endothelial cells and vascular smooth muscle cells to relatively high physiological shear stress has antiproliferative and vasoprotective effects. The present study hypothesizes that EECP inhibits intimal hyperplasia and atherogenesis by modifying shear stress-responsive gene expression. Methods and Results-Thirty-five male pigs were randomly assigned to 3 groups: high-cholesterol diet (nϭ11), high-cholesterol diet plus EECP (nϭ17), and usual diet (control; nϭ7). The coronary arteries and aortas were collected for histopathological study and immunohistochemical and Western blot analysis. The peak diastolic arterial wall shear stress during EECP increased significantly compared with before EECP (49.62Ϯ10.71 versus 23.92Ϯ7.28 dyne/cm 2 ; PϽ0.001). Intimal hyperplasia was observed in the coronary arteries of the high-cholesterol diet group, whereas in animals receiving EECP, the intima-to-media area ratio was significantly decreased by 41.59% (21.27Ϯ10.00% versus 36.41Ϯ16.69%; Pϭ0.008). Hypercholesterolemia attenuated the protein expression of endothelial NO synthase and enhanced the phosphorylation of extracellular signal-regulated kinases 1/2. EECP treatment alleviated these adverse changes. Conclusions-EECP reduces hypercholesterolemia-induced endothelial damage, arrests vascular smooth muscle cell proliferation and migration, decreases proliferating cell nuclear antigen proliferative index, suppresses extracellular matrix formation, and eventually inhibits intimal hyperplasia and the development of atherosclerosis by increasing the arterial wall shear stress, which in turn activates the endothelial NO synthase/NO pathway and probably suppresses extracellular signal-regulated kinases 1/2 overactivation. (Circulation. 2007;116:526-534.)

Low-amplitude pulses to the circulation through periodic acceleration induces endothelial-dependent vasodilatation

“…These findings are consistent with pG z activation of the Akt/PI3K pathway as a stimulus to eNOS activity, the latter via induced pulsations with circumferential stretch on the vascular endothelium. Our results also agree with in vitro endothelial cell culture findings of other investigators, who showed that pulsatile shear stress upregulates eNOS activity via the Akt/PI3K pathway (32,41,45,57).…”

“…In humans, descent of the dicrotic notch of digital and aortic pulse waves has been observed with nitrate and albuterol administration, as well as with exercise (10,26,29,39,42,46). This finding is mediated through the action of NO, since inhibition of NO synthesis with N G -nitro-L-arginine methyl ester (L-NAME) or N G -monomethyl-L-arginine prevents descent of the dicrotic notch after acetylcholine or albuterol administration in rabbits and humans, respectively (26, 52).Our purpose was to assess whether pG z applied to rats serves as a means of producing endothelial-dependent vasodilatation and to test whether such an effect is mediated, in part, via the well-known shear stress induced Akt/phosphatidylinositol 3-kinase (PI3K) pathway for NO production (13,55,57). …”

“…Our purpose was to assess whether pG z applied to rats serves as a means of producing endothelial-dependent vasodilatation and to test whether such an effect is mediated, in part, via the well-known shear stress induced Akt/phosphatidylinositol 3-kinase (PI3K) pathway for NO production (13,55,57).…”

Enhanced external counterpulsation creates acute blood flow patterns responsible for improved flow-mediated dilation in humans

“…4,8,10 Although changes in aortic and coronary hemodynamics have been proposed as primary hypotheses for the central changes after EECP, just a few studies have focused on the peripheral hemodynamics. [11][12][13][14] More specifically, acute blood flow patterns created by cuff compressions and their impact on peripheral endothelial function have not been studied in humans. The present study aims to determine if there is any acute peripheral vascular adaptation after a single 45-min session of EECP.…”

“…Finally, animal and human studies, [11][12][13] and mathematical models 14 have shown that EECP produces an increased retrograde blood flow and blood flow velocity in the lower extremities. Interestingly, there are some contradictory results when measuring endothelial function after retrograde flow.…”