Lysophosphatidic acid (LPA) via transactivation dependent signalling pathways contributes to a plethora of physiological and pathophysiological responses. In the vasculature, hyperelongation of glycosaminoglycan (GAG) chains on proteoglycans leads to lipid retention in the intima resulting in the early pathogenesis of atherosclerosis. Therefore, we investigated and defined the contribution of transactivation dependent signalling in LPA mediated GAG chain hyperelongation in human vascular smooth muscle cells (VSMCs).

LPA acting via the LPA receptor 5 (LPAR5) transactivates the TGFBR1 to stimulate the mRNA expression of GAG initiation and elongation genes xylosyltransferase-1 (XYLT1) and chondroitin 6-sulfotransferase-1 (CHST3), respectively. We found that LPA stimulates ROS and Akt signalling in VSMCs, however they are not associated in LPAR5 transactivation of the TGFBR1. We observed that LPA via ROCK dependent pathways transactivates the TGFBR1 to stimulate genes associated with GAG chain elongation. We demonstrate that GPCR transactivation of the TGFBR1 occurs via a universal biochemical mechanism and the identified effectors represent potential therapeutic targets to inhibit pathophysiological effects of GPCR transactivation of the TGFBR1.

溶血磷脂酸 (LPA) 通过反式激活依赖性信号通路导致大量的生理和病理生理反应。在脉管系统中，蛋白聚糖上糖胺聚糖 (GAG) 链的过度伸长导致脂质滞留在内膜中，从而导致动脉粥样硬化的早期发病机制。因此，我们研究并定义了反式激活依赖性信号在 LPA 介导的人血管平滑肌细胞 (VSMC) 中 GAG 链超伸长中的作用。

LPA 通过 LPA 受体 5 (LPAR5) 反式激活 TGFBR1，从而分别刺激 GAG 起始和延伸基因木糖基转移酶-1 ( XYLT1 ) 和软骨素 6-磺基转移酶-1 ( CHST3 ) 的 mRNA 表达。我们发现 LPA 刺激 VSMC 中的 ROS 和 Akt 信号传导，但它们与 TGFBR1 的 LPAR5 反式激活无关。我们观察到 LPA 通过 ROCK 依赖性途径反式激活 TGFBR1，从而刺激与 GAG 链伸长相关的基因。我们证明 TGFBR1 的 GPCR 反式激活是通过通用的生化机制发生的，并且已确定的效应器代表了抑制 TGFBR1 的 GPCR 反式激活的病理生理学效应的潜在治疗靶点。