Lemaster Kent A, Farid Zahra, Brock Robert W, Shrader Carl D, Goldman Daniel, Jackson Dwayne N, Frisbee Jefferson C
Department of Medical Biophysics, Transdisciplinary Program in Vascular Health, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.
Departments of Physiology and Pharmacology, West Virginia University HSC, Morgantown, WV, USA.
J Physiol. 2017 Aug 1;595(15):5159-5174. doi: 10.1113/JP274291. Epub 2017 Jul 5.
With the development of the metabolic syndrome, both post-capillary and collecting venular dilator reactivity within the skeletal muscle of obese Zucker rats (OZR) is impaired. The impaired dilator reactivity in OZR reflects a loss in venular nitric oxide and PGI bioavailability, associated with the chronic elevation in oxidant stress. Additionally, with the impaired dilator responses, a modest increase in adrenergic constriction combined with an elevated thromboxane A production may contribute to impaired functional dilator and hyperaemic responses at the venular level. For the shift in skeletal muscle venular function with development of the metabolic syndrome, issues such as aggregate microvascular perfusion resistance, mass transport and exchange within with capillary networks, and fluid handling across the microcirculation are compelling avenues for future investigation.
While research into vascular outcomes of the metabolic syndrome has focused on arterial/arteriolar and capillary levels, investigation into venular function and how this impacts responses has received little attention. Using the in situ cremaster muscle of obese Zucker rats (OZR; with lean Zucker rats (LZR) as controls), we determined indices of venular function. At ∼17 weeks of age, skeletal muscle post-capillary venular density was reduced by ∼20% in LZR vs. OZR, although there was no evidence of remodelling of the venular wall. Venular tone at ∼25 μm (post-capillary) and ∼75 μm (collecting) diameter was elevated in OZR vs. LZR. Venular dilatation to acetylcholine was blunted in OZR vs. LZR due to increased oxidant stress-based loss of nitric oxide bioavailability (post-capillary) and increased α - (and α -) mediated constrictor tone (collecting). Venular constrictor responses in OZR were comparable to LZR for most stimuli, although constriction to α -adrenoreceptor stimulation was elevated. In response to field stimulation of the cremaster muscle (0.5, 1, 3 Hz), venular dilator and hyperaemic responses to lower frequencies were blunted in OZR, but responses at 3 Hz were similar between strains. Venous production of TxA was higher in OZR than LZR and significantly higher than PGI production in either following arachidonic acid challenge. These results suggest that multi-faceted alterations to skeletal muscle venular function in OZR may contribute to alterations in upstream capillary pressure profiles and the transcapillary exchange of solutes and water under conditions of metabolic syndrome.
随着代谢综合征的发展，肥胖Zucker大鼠（OZR）骨骼肌内毛细血管后和集合小静脉的扩张反应性均受损。OZR中受损的扩张反应性反映了小静脉一氧化氮和前列环素生物利用度的丧失，这与氧化应激的慢性升高有关。此外，随着扩张反应受损，肾上腺素能收缩的适度增加与血栓素A生成的升高可能导致小静脉水平的功能性扩张和充血反应受损。对于随着代谢综合征发展而出现的骨骼肌小静脉功能变化，诸如总微血管灌注阻力、毛细血管网络内的物质运输和交换以及微循环中的液体处理等问题是未来研究的重要方向。
虽然对代谢综合征血管结局的研究主要集中在动脉/小动脉和毛细血管水平，但对小静脉功能及其如何影响反应的研究却很少受到关注。我们以肥胖Zucker大鼠（OZR；以瘦Zucker大鼠（LZR）作为对照）的原位提睾肌为研究对象，测定了小静脉功能指标。在约17周龄时，与OZR相比，LZR的骨骼肌毛细血管后小静脉密度降低了约20%，尽管没有小静脉壁重塑的证据。与LZR相比，OZR中直径约25μm（毛细血管后）和约75μm（集合）的小静脉张力升高。与LZR相比，OZR对乙酰胆碱的小静脉扩张反应减弱，这是由于基于氧化应激的一氧化氮生物利用度丧失增加（毛细血管后）以及α-（和α-）介导的收缩张力增加（集合）。对于大多数刺激，OZR的小静脉收缩反应与LZR相当，尽管对α-肾上腺素能受体刺激的收缩反应升高。响应提睾肌的场刺激（0.5、1、3Hz），OZR对较低频率的小静脉扩张和充血反应减弱，但在3Hz时两个品系的反应相似。在花生四烯酸刺激后，OZR的静脉血栓素A生成高于LZR，且显著高于两者中的前列环素生成。这些结果表明，OZR骨骼肌小静脉功能的多方面改变可能导致代谢综合征条件下上游毛细血管压力分布以及溶质和水的跨毛细血管交换发生改变。
