Effects of bariatric surgery on human small artery function: evidence for reduction in perivascular adipocyte inflammation, and the restoration of normal anticontractile activity despite persistent obesity

Abstract

Objectives: The aim of this study was to investigate the effects of bariatric surgery on small artery function and the mechanisms underlying this.

Background: In lean healthy humans, perivascular adipose tissue (PVAT) exerts an anticontractile effect on adjacent small arteries, but this is lost in obesity-associated conditions such as the metabolic syndrome and type II diabetes where there is evidence of adipocyte inflammation and increased oxidative stress.

Methods: Segments of small subcutaneous artery and perivascular fat were harvested from severely obese individuals before (n = 20) and 6 months after bariatric surgery (n = 15). Small artery contractile function was examined in vitro with wire myography, and perivascular adipose tissue (PVAT) morphology was assessed with immunohistochemistry.

Results: The anticontractile activity of PVAT was lost in obese patients before surgery when compared with healthy volunteers and was restored 6 months after bariatric surgery. In vitro protocols with superoxide dismutase and catalase rescued PVAT anticontractile function in tissue from obese individuals before surgery. The improvement in anticontractile function after surgery was accompanied by improvements in insulin sensitivity, serum glycemic indexes, inflammatory cytokines, adipokine profile, and systolic blood pressure together with increased PVAT adiponectin and nitric oxide bioavailability and reduced macrophage infiltration and inflammation. These changes were observed despite the patients remaining severely obese.

Conclusions: Bariatric surgery and its attendant improvements in weight, blood pressure, inflammation, and metabolism collectively reverse the obesity-induced alteration to PVAT anticontractile function. This reversal is attributable to reductions in local adipose inflammation and oxidative stress with improved adiponectin and nitric oxide bioavailability.

Figure 1

Effect of PVAT on Small Artery Tone Before and After Surgery (A) In pre-surgery patients, the presence of perivascular adipose tissue (PVAT) did not affect vessel contractility as compared with skeletonized segments of the same vessel (n = 20, p = 0.95). (B) In post-surgery patients, the presence of PVAT had a significant anticontractile effect on the small artery contractility (n = 15, ∗p < 0.01). KPSS = high-potassium physiological saline; Log [NE] (M) = log of the molar concentration of norepinephrine.

Figure 2

Pharmacological Protocols on PVAT Pre-Surgery and Post-Surgery (A) Blocking peptide for polyclonal antibody to adiponectin receptor 1 increases vessel contractility to norepinephrine (n = 7, p <0.0001). (B) Incubation with superoxide dismutase (SOD) and catalase rescues the PVAT anticontractile effect in samples taken from pre-surgery patients (n = 7, p < 0.001). (C) Post-surgery, inhibition of nitric oxide synthase by incubation with N5-[imino(methylamino)methyl]-L-ornithine, citrate (L-NMMA) leads to increased contractility of vessel segments with intact PVAT (n = 4, ∗p < 0.001). Abbreviations as in Figure 1.

Figure 3

Subcutaneous Adipose Tissue Before and After Surgery Inflammatory infiltrates composed mostly of macrophages were present in wreath-like arrangements (A), in groups (B), or were scattered. Staining for macrophage marker (CD68 (KP1) (C) allowed for performing cell counts. There was a significant reduction in the number of CD-68 staining macrophages post-surgery (n = 14, 7.3 ± 1.1 vs. 4.1 ± 0.7, ∗p < 0.01) (D). Scale bar = 20 μm.

Figure 4

Assessment of TNF-α Staining and Adipocyte Size Pre- and Post-Surgery Immunostaining for tumor necrosis factor (TNF)-α showed that adipocytes themselves were positive for this cytokine, to a higher extent pre-surgery (A) than post-surgery (B). Note positive staining of microvessels in the pre-operative biopsy. There is a significant reduction in the percentage of adipose tissue area that stains for TNF-α pre-surgery versus post-surgery (1.41 ± 0.34 vs. 0.68 ± 0.09, ∗p < 0.05) (C). The average adipocyte area was 7,672 ± 369.6 μm² pre-surgery and 3,955 ± 207.5 μm² (∗p < 0.0001) post-surgery (D). Scale bar = 20 μm.

Figure 5

Background and Conclusions (A) In obesity there is an increase in perivascular adipose tissue (PVAT) levels of inflammatory cells and cytokines as well as increase in levels of leptin. (B) We conclude that, after bariatric surgery, there is an increase in adiponectin levels and nitric oxide bioavailability in PVAT and reduction in tissue inflammation, which contributes to restoration of PVAT anticontractile function. MCP = monocyte chemoattractant protein; TNF = tumor necrosis factor.