Catechin prevents severe dyslipidemia-associated changes in wall biomechanics of cerebral arteries in LDLr-/-:hApoB+/+ mice and improves cerebral blood flow

Abstract

Endothelial dysfunction and oxidative stress contribute to the atherosclerotic process that includes stiffening of large peripheral arteries. In contrast, our laboratory previously reported a paradoxical increase in cerebrovascular compliance in LDLr(-/-):hApoB(+/+) atherosclerotic (ATX) mice (7). We hypothesized that prevention of cerebral artery endothelial dysfunction with a chronic dietary antioxidant intake would normalize the changes in cerebral artery wall structure and biomechanics and prevent the decline in basal cerebral blood flow associated with atherosclerosis. Three-month-old ATX mice were treated, or not, for 3 mo with the polyphenol (+)-catechin (CAT; 30 mg·kg(-1)·day(-1)) and compared with wild-type controls. In isolated, pressurized cerebral arteries from ATX mice, CAT prevented endothelial dysfunction (deterioration of endothelium-dependent, flow-mediated dilations; P < 0.05), the inward hypertrophic structural remodeling (increase in the wall-to-lumen ratio; P < 0.05), and the rise in cerebrovascular compliance (rightward shift of the stress-strain curve measured in passive conditions, reflecting mechanical properties of the arterial wall; P < 0.05). Doppler optical coherence tomography imaging in vivo confirmed these findings, showing that cerebral compliance was higher in ATX mice and normalized by CAT (P < 0.05). CAT also prevented basal cerebral hypoperfusion in ATX mice (P < 0.05). Active remodeling of the cerebrovascular wall in ATX mice was further suggested by the increase (P < 0.05) in pro-metalloproteinase-9 activity, which was normalized by CAT. We conclude that, by preserving the endothelial function, a chronic treatment with CAT prevents the deleterious effect of severe dyslipidemia on cerebral artery wall structure and biomechanical properties, contributing to preserving resting cerebral blood flow.

Fig. 1

Effect of a chronic treatment with (+)-catechin (CAT) of 6-mo LDLr^−/−:hApoB^+/+ [atherosclerotic (ATX)] mice, on the arterial compliance expressed as the stress-strain relationship (A and B) and on the distensibility expressed as incremental distensibility (ID; %/mmHg; C and D) in carotid arteries (A and C) and cerebral arteries (B and D). Values are means ± SE of 5–9 mice for carotid arteries and of 10 –17 mice for cerebral arteries. WT, wild type. *P < 0.05 vs. WT mice. *P < 0.05 vs. ATX mice.

Fig. 2

Effect of a chronic treatment with CAT of 6-mo LDLr^−/−:hApoB^+/+ (ATX) mice, on the structural changes occurring in cerebral arteries. A: vessel lumen diameter; B: vessel external diameter; C: vessel wall thickness; D: wall-to-lumen ratio. Values are means ± SE of 10 –17 mice. *P < 0.05 vs. WT mice. ^αP < 0.05 vs. ATX mice.

Fig. 3

Effect of chronic treatment with CAT of 6-mo LDLr^−/−:hApoB^+/+ (ATX) mice, on flow-mediated endothelium-dependent dilations induced by increasing shear stresses (dyn/cm²) of pressurized cerebral arteries. Values are means ± SE of 10 –17 mice. *P < 0.05 vs. WT mice. ^αP < 0.05 vs. ATX mice.

Fig. 4

Effect of a chronic treatment with CAT of 6-mo LDLr^−/−:hApoB^+/+ (ATX) mice on in vivo cerebral compliance expressed as the local compliance evaluator (nl/Pa) (A) and basal cerebral blood flow (CBF; nl/s) normalized to arterial area (mm²) and evaluated in the microvasculature (B). A: values are means ± SE of 10 mice for WT and ATX mice and of 4 mice for ATX+CAT mice. B: values are means ± SE of 78 vessels for WT mice, 25 for ATX mice, and 88 for ATX+CAT mice. *P < 0.05 vs. WT mice. ^αP < 0.05 vs. ATX mice.

Fig. 5

A: representative example of zymography illustrating pro-matrix metalloproteinase (MMP)-9 activities of cerebral vessels from WT, LDLr^−/−: hApoB^+/+ (ATX) mice, and ATX treated with CAT. B: each set of experiment was normalized to a reference sample (loaded in every experiments). Values are means ± SE of 6 mice. au, Arbitrary units. *P < 0.05 vs. WT mice. ^αP < 0.05 vs. ATX mice.

Fig. 6

A: effect of a chronic treatment of 6-mo LDLr^−/−:hApoB^+/+ (ATX) mice with CAT on plasma VEGF level. B: representative example of Western blot illustrating VEGF protein expression of total cerebral vessels from WT and ATX mice treated, or not, with CAT. C: graph represents the protein expression normalized to a reference sample (loaded in every experiment) and after normalization with smooth muscle α-actin. Values are means ± SE of 4 –5 mice. ^αP < 0.05 vs. ATX mice.