Menon Nithin J, Halvorson Brayden D, Alimorad Gabrielle H, Frisbee Jefferson C, Lizotte Daniel J, Ward Aaron D, Goldman Daniel, Chantler Paul D, Frisbee Stephanie J
Department of Medical Biophysics, London, ON, Canada.
Department of Epidemiology and Biostatistics, London, ON, Canada.
Front Pharmacol. 2023 Jan 25;14:1104568. doi: 10.3389/fphar.2023.1104568. eCollection 2023.
While a thorough understanding of microvascular function in health and how it becomes compromised with progression of disease risk is critical for developing effective therapeutic interventions, our ability to accurately assess the beneficial impact of pharmacological interventions to improve outcomes is vital. Here we introduce a novel Vascular Health Index (VHI) that allows for simultaneous assessment of changes to vascular reactivity/endothelial function, vascular wall mechanics and microvessel density within cerebral and skeletal muscle vascular networks with progression of metabolic disease in obese Zucker rats (OZR); under control conditions and following pharmacological interventions of clinical relevance. Outcomes are compared to "healthy" conditions in lean Zucker rats. We detail the calculation of vascular health index, full assessments of validity, and describe progressive changes to vascular health index over the development of metabolic disease in obese Zucker rats. Further, we detail the improvement to cerebral and skeletal muscle vascular health index following chronic treatment of obese Zucker rats with anti-hypertensive (15%-52% for skeletal muscle vascular health index; 12%-48% for cerebral vascular health index; < 0.05 for both), anti-dyslipidemic (13%-48% for skeletal muscle vascular health index; < 0.05), anti-diabetic (12%-32% for cerebral vascular health index; < 0.05) and anti-oxidant/inflammation (41%-64% for skeletal muscle vascular health index; 29%-42% for cerebral vascular health index; < 0.05 for both) drugs. The results present the effectiveness of mechanistically diverse interventions to improve cerebral or skeletal muscle vascular health index in obese Zucker rats and provide insight into the superiority of some pharmacological agents despite similar effectiveness in terms of impact on intended targets. In addition, we demonstrate the utility of including a wider, more integrative approach to the study of microvasculopathy under settings of elevated disease risk and following pharmacological intervention. A major benefit of integrating vascular health index is an increased understanding of the development, timing and efficacy of interventions through greater insight into integrated microvascular function in combination with individual, higher resolution metrics.
虽然深入了解健康状态下的微血管功能以及随着疾病风险进展其如何受损对于开发有效的治疗干预措施至关重要，但我们准确评估药物干预改善预后的有益影响的能力也至关重要。在此，我们引入一种新型血管健康指数（VHI），它能够在肥胖 Zucker 大鼠（OZR）代谢疾病进展过程中，同时评估脑和骨骼肌血管网络内血管反应性/内皮功能、血管壁力学以及微血管密度的变化；在对照条件下以及进行具有临床相关性的药物干预之后。将结果与瘦 Zucker 大鼠的“健康”状况进行比较。我们详细介绍了血管健康指数的计算方法、有效性的全面评估，并描述了肥胖 Zucker 大鼠代谢疾病发展过程中血管健康指数的渐进性变化。此外，我们详细阐述了用抗高血压药物（骨骼肌血管健康指数提高 15% - 52%；脑血管健康指数提高 12% - 48%；两者均 P < 0.05）、抗血脂异常药物（骨骼肌血管健康指数提高 13% - 48%；P < 0.05）、抗糖尿病药物（脑血管健康指数提高 12% - 32%；P < 0.05）以及抗氧化/抗炎药物（骨骼肌血管健康指数提高 41% - 64%；脑血管健康指数提高 29% - 42%；两者均 P < 0.05）长期治疗肥胖 Zucker 大鼠后，脑和骨骼肌血管健康指数的改善情况。结果表明，在肥胖 Zucker 大鼠中，机制多样的干预措施对改善脑或骨骼肌血管健康指数是有效的，并且尽管在对预期靶点的影响方面效果相似，但能深入了解某些药物的优越性。此外，我们证明了在疾病风险升高以及药物干预的情况下，采用更广泛、更综合的方法研究微血管病变的实用性。整合血管健康指数的一个主要益处是，通过更深入了解综合微血管功能以及个体的高分辨率指标，能更好地理解干预措施的发展、时机和疗效。
