微血管病變在糖尿病神經病理的分子機制

Abstract

為了解糖尿病性神經病變中微血管病變的病理學和分子機制，我們系統性和定量性地分析了腓腸神經微血管和神經病理的形態學。在糖尿病的神經內膜中，顯著的微血管病變表現為微血管管腔面積減小，微血管基底膜厚度增加以及表現纖維蛋白血管比例增加。此外，微血管基底膜厚度和表現纖維蛋白血管的比例與糖尿病神經中小髓鞘髓神經纖維密度相關。在糖尿病神經中，存在顯著的巨噬細胞和T細胞浸潤，並且CD40表達增加。此外，我們也發現缺氧誘導因子-1α（HIF-1α），絲裂原活化蛋白激酶—活化蛋白激酶2（MK2）和磷酸酶和張力蛋白同系物（PTEN）在糖尿病神經中顯著增加。HIF-1α與小髓鞘纖維密度和微血管腔面積密切相關，而MK2和PTEN均與糖尿病神經中微血管基底膜厚度相關。在暴露於高葡萄糖培養基的人類臍靜脈內皮細胞（HUVEC）的細胞培養物中進一步觀察到上述分子的表現增加和高血糖的環境有關。在高葡萄糖暴露後，CD40的抑制減弱了HIF-1α和PTEN的表達，進一步證實了上述分子之間的上下游關係。在糖尿病神經中，本研究表明（1）微血管病變，血栓形成和發炎細胞浸潤與神經退行性病變的相關性，以及（2）CD40是調控和微血管病變嚴重程度有關的HIF-1α和PTEN上游的關鍵分子。

To understand the pathology and molecular signatures of microangiopathy in diabetic neuropathy, we systemically and quantitatively examined the morphometry of microvascular and nerve pathologies of sural nerves. In the endoneurium of diabetic nerves, prominent microangiopathy was evidenced by reduced capillary luminal area, increased capillary basement membrane thickness, and increased proportion of fibrin(+) blood vessels. Furthermore, capillary basement membrane thickness and the proportion of fibrin(+) blood vessels were correlated with small myelinated fiber density in diabetic nerves. In diabetic nerves, there was significant macrophage and T cell infiltration, and cluster of differentiation 40 (CD40) expression was increased. Hypoxia-inducible factor-1α (HIF-1α), mitogen-activated protein kinase-activated protein kinase 2 (MK2), and phosphatase and tensin homolog (PTEN) were upregulated in diabetic nerves. HIF-1α was correlated with small myelinated fiber density and capillary luminal area, while both MK2 and PTEN were correlated with capillary basement membrane thickness in diabetic nerves. The molecular cascades were further demonstrated and replicated in cell cultures of human umbilical vein endothelial cells (HUVECs) exposed to high-glucose medium. The silencing of CD40 attenuated HIF-1α and PTEN following high-glucose exposure. In diabetic nerves, this study demonstrated (1) the association of microangiopathy, thrombosis, and inflammatory infiltrates with nerve degeneration and (2) CD40 as a key molecule for the upregulation of HIF-1α and PTEN underlying the severity of microangiopathy.