Loai Sadi, Sun Xuetao, Husain Mansoor, Laflamme Michael A, Yeger Herman, Nunes Sara S, Cheng Hai-Ling Margaret
Institute of Biomedical Engineering, University of Toronto, Toronto, ON, Canada.
Translational Biology and Engineering Program, Ted Rogers Centre for Heart Research, Toronto, ON, Canada.
Front Cardiovasc Med. 2022 May 18;9:886687. doi: 10.3389/fcvm.2022.886687. eCollection 2022.
To uncover sex-related microvascular abnormalities that underlie the early presentation of reduced perfusion in leg skeletal muscle in a type II rat model of diabetic cardiomyopathy.
Diabetes was induced using a non-obese, diet-based, low-dose streptozotocin model in adult female (18 diabetic, 9 control) and male rats (29 diabetic, 11 control). Time-course monitoring over 12 months following diabetes induction was performed using echocardiography, treadmill exercise, photoacoustic imaging, flow-mediated dilation (FMD), histopathology, and immunohistochemistry. Diabetic rats maintained normal weights. Hypertension appeared late in both diabetic males (7 months) and females (10 months), while only diabetic males had elevated cholesterol (7 months). On echocardiography, all diabetic animals maintained normal ejection fraction and exhibited diastolic dysfunction, mild systolic dysfunction, and a slightly enlarged left ventricle. Exercise tolerance declined progressively and early in males (4 months), later in females (8 months); FMD showed lower baseline femoral arterial flow but unchanged reactivity in both sexes (5 months); and photoacoustic imaging showed lower tissue oxygen saturation in the legs of diabetic males (4 months) and diabetic females (10 months). Myocardial perfusion was normal in both sexes. Histopathology at the final timepoint of Month 10 (males) and Month 12 (females) revealed that myocardial microvasculature was normal in both vessel density and structure, thus explaining normal perfusion on imaging. However, leg muscle microvasculature exhibited perivascular smooth muscle thickening around small arterioles in diabetic females and around large arterioles in diabetic males, explaining the depressed readings on photoacoustic and FMD. Histology also confirmed the absence of commonly reported HFpEF markers, including microvessel rarefaction, myocardial fibrosis, and left ventricular hypertrophy.
Exercise intolerance manifesting early in the progression of diabetic cardiomyopathy can be attributed to decreased perfusion to the leg skeletal muscle due to perivascular smooth muscle thickening around small arterioles in females and large arterioles in males. This microvascular abnormality was absent in the myocardium, where perfusion levels remained normal throughout the study. We conclude that although skeletal muscle microvascular dysfunction of the vasculature presents at different levels depending on sex, it consistently presents early in both sexes prior to overt cardiac changes such as rarefaction, fibrosis, or hypertrophy.
在糖尿病性心肌病II型大鼠模型中，揭示与性别相关的微血管异常，这些异常是腿部骨骼肌灌注减少早期表现的基础。
采用非肥胖、基于饮食的低剂量链脲佐菌素模型诱导成年雌性大鼠（18只糖尿病大鼠，9只对照大鼠）和雄性大鼠（29只糖尿病大鼠，11只对照大鼠）患糖尿病。在诱导糖尿病后的12个月内，使用超声心动图、跑步机运动、光声成像、血流介导的血管舒张（FMD）、组织病理学和免疫组织化学进行时间进程监测。糖尿病大鼠体重维持正常。糖尿病雄性大鼠（7个月）和雌性大鼠（10个月）后期出现高血压，而只有糖尿病雄性大鼠胆固醇升高（7个月）。超声心动图显示，所有糖尿病动物的射血分数均正常，但存在舒张功能障碍、轻度收缩功能障碍和左心室轻度扩大。运动耐量在雄性大鼠中早期（4个月）逐渐下降，在雌性大鼠中后期（8个月）逐渐下降；FMD显示两性股动脉基线血流较低，但反应性未改变（5个月）；光声成像显示糖尿病雄性大鼠（4个月）和糖尿病雌性大鼠（10个月）腿部组织氧饱和度较低。两性的心肌灌注均正常。在第10个月（雄性）和第12个月（雌性）的最后时间点进行的组织病理学检查显示，心肌微血管在血管密度和结构上均正常，从而解释了成像时灌注正常的原因。然而，腿部肌肉微血管在糖尿病雌性大鼠的小动脉周围和糖尿病雄性大鼠的大动脉周围表现出血管周围平滑肌增厚，这解释了光声和FMD测量值降低的原因。组织学检查还证实不存在常见报道的射血分数保留的心力衰竭（HFpEF）标志物，包括微血管稀疏、心肌纤维化和左心室肥厚。
糖尿病性心肌病进展早期出现的运动不耐受可归因于雌性大鼠小动脉周围和雄性大鼠大动脉周围血管周围平滑肌增厚导致的腿部骨骼肌灌注减少。心肌中不存在这种微血管异常，在整个研究过程中心肌灌注水平保持正常。我们得出结论，尽管血管的骨骼肌微血管功能障碍根据性别在不同水平出现，但在明显的心脏变化（如稀疏、纤维化或肥大）之前，两性均在早期一致出现。
