Role of Chronic Stress and Exercise on Microvascular Function in Metabolic Syndrome

Abstract

Purpose: The present study examined the effect of unpredictable chronic mild stress (UCMS) on peripheral microvessel function in healthy and metabolic syndrome (MetS) rodents and whether exercise training could prevent the vascular dysfunction associated with UCMS.

Methods: Lean and obese (model of MetS) Zucker rats (LZR and OZR) were exposed to 8 wk of UCMS, exercise (Ex), UCMS + Ex, or control conditions. At the end of the intervention, gracilis arterioles (GA) were isolated and hung in a pressurized myobath to assess endothelium-dependent (EDD) and endothelium-independent (EID) dilation. Levels of nitric oxide (NO) and reactive oxygen species (ROS) were measured through 4-amino-5-methylamino-2',7'-difluorofluorescein diacetate and dihydroethidium staining, respectively.

Results: Compared with LZR controls, EDD and EID were lower (P = 0.0001) in LZR-UCMS. The OZR-Ex group had a higher EDD (P = 0.0001) and EID (P = 0.003) compared with OZR controls, whereas only a difference in EDD (P = 0.01) was noted between the LZR-control and LZR-Ex groups. Importantly, EDD and EID were higher in the LZR (P = 0.0001; P = 0.02) and OZR (P = 0.0001; P = 0.02) UCMS + Ex groups compared with UCMS alone. Lower NO bioavailability and higher ROS were noted in the LZR-UCMS group (P = 0.0001), but not OZR-UCMS, compared with controls. The Ex and UCMS-Ex groups had higher NO bioavailability (P = 0.0001) compared with the control and UCMS groups, but ROS levels remained high.

Conclusions: The comorbidity between UCMS and MetS does not exacerbate the effects of one another on GA EDD responses, but does lead to the development of other vasculopathy adaptations, which can be partially explained by alterations in NO and ROS production. Importantly, exercise training alleviates most of the negative effects of UCMS on GA function.

Figure 1. The effects of UCMS and Ex on GA reactivity

A) Assessment of endothelium-dependent dilation (EDD) to a maximal does of Ach (10⁻⁶M); B) endothelium-independent dilation (EID) to a maximal does of SNP (10⁻⁶M); and C) GA constriction to a maximal does of PE (10⁻⁷M). n = 6–8/group. Mean ± SD. ^*p<0.05 vs. control, ^#p<0.05 vs. UCMS, ^p<0.05 vs. Ex, °p<0.05 vs. matched treatment group in opposite species (i.e., LZR vs. OZR), ^‡p<0.05 species (LZR vs. OZR) by group (Con, UCMS, Ex, UCMS+Ex) interaction. Please see text for additional details.

Figure 2. The effects of acute TEMPOL or L-NAME incubation on GA reactivity. The effects of

acute TEMPOL incubation on EDD reactivity in LZR (A) and OZR (B). The effects of acute L-NAME incubation on EDD reactivity in LZR (C) and OZR (D). n = 6–8/group. Mean ± SD. ^*p<0.01 vs. control, ^#p<0.01 vs. UCMS, ^p<0.05 vs. exercise, ⁺p<0.05 within group comparison for change in TEMPOL or L-NAME. ^‡p<0.05 species (LZR vs. OZR) by group (Con, UCMS, Ex, UCMS+Ex) interaction. See text for additional details.

Figure 3. The effects of UCMS and Ex on NO and ROS levels

A) NO levels in the aorta as determined by DAF-FM diacetate assay; and B) DHE staining indicating ROS levels in the aortas of each group. Mean ± SD. ^*p<0.05 vs. control, ^#p<0.05 vs. UCMS, ^p<0.05 vs. exercise, °p<0.05 vs. matched treatment group in opposite species. ^‡p<0.05 species (LZR vs. OZR) by group (Con, UCMS, Ex, UCMS+Ex) interaction. See text for additional details.