Pathophysiological Regulation of Vascular Smooth Muscle Cells by Prostaglandin F2α-dependent Activation of Phospholipase C-β3

Atherosclerosis is an obstructive vessel disease mainly caused by chronic arterial inflammation to which the proliferation and migration of vascular smooth muscle cells (VSMCs) is the main pathological response. In the present study, the primary responsible inflammatory cytokine and its signaling pathway was investigated. The proliferation and migration of VSMCs was significantly enhanced by the prostaglandin $F_{2{\alpha}}$ ($PGF_{2{\alpha}}$), while neither was affected by tumor necrosis factor ${\alpha}$. Prostacyclin $I_2$ was seen to enhance the proliferation of VSMCs while simultaneously suppressing their migration. Both prostaglandin $D_2$ and prostaglandin $E_2$ significantly enhanced the migration of VSMCs, however, proliferation was not affected by either of them. The proliferation and migration of VSMCs stimulated by $PGF_{2{\alpha}}$ progressed in a dose-dependent manner; the $EC_{50}$ value of both proliferation and migration was $0.1{\mu}M$. VSMCs highly expressed the phospholipase isoform $C-{\beta}3$ ($PLC-{\beta}3$) while others such as $PLC-{\beta}1$, $PLC-{\beta}2$, and $PLC-{\beta}4$ were not expressed. Inhibition of the PLCs by U73122 completely blocked the $PGF_{2{\alpha}}$-induced migration of VSMCs, and, in addition, silencing $PLC-{\beta}3$ significantly diminished the $PGF_{2{\alpha}}$-induced proliferation and migration of VSMCs. Given these results, we suggest that $PGF_{2{\alpha}}$ plays a crucial role in the proliferation and migration of VSMCs, and activation of $PLC-{\beta}3$ could be involved in their $PGF_{2{\alpha}}$-dependent migration.

Prostaglandin F2α 의존적 phospholipase C-β3 활성화에 의한 혈관평활근세포의 병태생리 조절 연구

죽상동맥경화는 대동맥의 만성염증에 의해 주로 발병되는 폐쇄동맥질환이다. 혈관평활근세포의 증식 및 이동은 죽상동맥경화 발병의 주된 병리적 반응이다. 본 연구에서는 죽상동맥경화 발병기전을 유도하는 표적 염증반응 물질의 탐색 및 이들에 의한 신호전달 기전을 연구하였다. 혈관평활근세포의 증식 및 이동은 prostaglandin $F_{2{\alpha}}$ ($PGF_{2{\alpha}}$)에 의해 의미 있게 증가하였으나 tumor necrosis factor ${\alpha}$ ($TNF{\alpha}$)에 의해서는 증가하지 않았다. Prostacyclin $I_2$ ($PGI_2$)는 혈관평활근세포의 증식은 촉진시켰으나 이동은 오히려 억제하였다. prostaglandin $D_2$ ($PGD_2$) 및 prostaglandin $E_2$ ($PGE_2$)는 혈관평활근세포의 증식을 촉진시켰으나 이동에는 영향을 미치지 않았다. $PGF_{2{\alpha}}$는 용량 의존적으로 혈관평활근세포의 증식 및 이동을 촉진시켰고 EC50는 약 $0.1{\mu}M$로 관찰되었다. 혈관평활근세포에서 phospholipase $C-{\beta}3$ ($PLC-{\beta}3$) 아형의 발현은 매우 높았으나 $PLC-{\beta}1$, $PLC-{\beta}2$, 및 $PLC-{\beta}4$의 발현은 관찰되지 않았다. U73122 처리를 통해 PLC의 활성을 억제하면 $PGF_{2{\alpha}}$에 의한 혈관평활근세포의 이동이 억제되었다. 또한 $PLC-{\beta}3$의 발현을 억제하면 $PGF_{2{\alpha}}$에 의한 혈관평활근세포의 증식 및 이동이 억제되었다. 이러한 결과들을 바탕으로 $PGF_{2{\alpha}}$ 는 혈관평활근세포의 증식 및 이동에 중요한 역할을 수행하고, 여기에는 $PLC-{\beta}3$가 필수적인 역할을 담당하고 있음을 제안한다.