Bou Khzam Lara, Son Ni-Huiping, Mullick Adam E, Abumrad Nada A, Goldberg Ira J
Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, NYU Langone Health New York, NY, USA.
Ionis Pharmaceuticals Carlsbad, CA, USA.
Am J Transl Res. 2020 Dec 15;12(12):7737-7761. eCollection 2020.
Endothelial cells (ECs) maintain vascular integrity and mediate vascular repair and angiogenesis, by which new blood vessels are formed from pre-existing blood vessels. Hyperglycemia has been shown to increase EC angiogenic potential. However, few studies have investigated effects of fatty acids (FAs) on EC angiogenesis. Cluster of differentiation 36 (CD36) is a FA transporter expressed by ECs, but its role in EC proliferation, migration, and angiogenesis is unknown. We sought to determine if circulating FAs regulate angiogenic function in a CD36-dependent manner. CD36-dependent effects of FAs on EC proliferation and migration of mouse heart ECs (MHECs) and lung ECs (MLECs) were studied. We used both silencing RNA and antisense oligonucleotides to reduce CD36 expression. Oleic acid (OA) did not affect EC proliferation, but significantly increased migration of ECs in wound healing experiments. CD36 knockdown prevented OA-induced increases in wound healing potential. In EC transwell migration experiments, OA increased recruitment and migration of ECs, an effect abolished by CD36 knockdown. Phospho-AMP-activated protein kinase (AMPK) increased in MHECs exposed to OA in a CD36-dependent manner. To test whether CD36 affects angiogenesis, we studied 21-day recovery in post-hindlimb ischemia. EC-specific CD36 knockout mice had reduced blood flow recovery as assessed by laser Doppler imaging. EC content in post-ischemic muscle, assessed from CD31 expression, increased in ischemic muscle of control mice. However, mice with EC-specific CD36 deletion lacked the increase in CD31 and matrix metalloprotease 9 expression observed in controls. EC expression of CD36 and its function in FA uptake modulate angiogenic function and response to ischemia, likely due to reduced activation of the AMPK pathway.
内皮细胞（ECs）维持血管完整性，并介导血管修复和血管生成，通过这一过程新血管由已有的血管形成。高血糖已被证明会增加内皮细胞的血管生成潜能。然而，很少有研究调查脂肪酸（FAs）对内皮细胞血管生成的影响。分化簇36（CD36）是一种由内皮细胞表达的脂肪酸转运蛋白，但其在内皮细胞增殖、迁移和血管生成中的作用尚不清楚。我们试图确定循环脂肪酸是否以CD36依赖的方式调节血管生成功能。研究了脂肪酸对小鼠心脏内皮细胞（MHECs）和肺内皮细胞（MLECs）增殖和迁移的CD36依赖效应。我们使用小干扰RNA和反义寡核苷酸来降低CD36的表达。油酸（OA）不影响内皮细胞增殖，但在伤口愈合实验中显著增加内皮细胞的迁移。CD36基因敲低可阻止OA诱导的伤口愈合潜能增加。在内皮细胞Transwell迁移实验中，OA增加了内皮细胞的募集和迁移，CD36基因敲低可消除这一效应。磷酸化的AMP激活蛋白激酶（AMPK）在暴露于OA的MHECs中以CD36依赖的方式增加。为了测试CD36是否影响血管生成，我们研究了后肢缺血21天的恢复情况。通过激光多普勒成像评估，内皮细胞特异性CD36基因敲除小鼠的血流恢复减少。从CD31表达评估，缺血后肌肉中的内皮细胞含量在对照小鼠的缺血肌肉中增加。然而，内皮细胞特异性CD36缺失的小鼠缺乏对照小鼠中观察到的CD31和基质金属蛋白酶9表达的增加。CD36在内皮细胞中的表达及其在脂肪酸摄取中的功能调节血管生成功能和对缺血的反应，可能是由于AMPK途径的激活减少。
