Diabetes- and hypertension-induced upregulation of concentrative nucleoside transporter-2 in endothelial cells

Abstract

Adenosine modulates a variety of vascular functions and adenosine homeostasis is controlled by nucleoside transporters. Nucleoside transporters are divided into 2 classes. The equilibrative nucleoside transporters (ENTs) are Na+ -independent and are VXEGLYLGHGLQWR W\SHVEDVHGRQWKHLUVHQVLWLYLWLHVWR > QLWUREHQ]\O WKLRO@ ȕ ' ribofuranosylpurine (NBMPR). The concentrative nucleoside transporters (CNTs) are Na+ -dependent and are subdivided into 3 types based on the substrate selectivity. In this study, the nucleoside transporters in vascular cells were characterized and their changes in diabetes and hypertension were investigated. )XQFWLRQDOVWXGLHVVKRZHGWKDW RIWKH>3 H]adenosine transport in human brain vascular endothelial cells (HBECs) was Na+ -dependent. In the Na+ -independent component, 80% was inhibited by NBMPR (10 nM, which inhibits ENT1 but not ENT2). However, the [3 H]adenosine transport in vascular smooth muscle cells (HBSMCs) was totally Na+ -independent and 95% of it was inhibited by NBMPR (10 nM). RT-PCR revealed the presence of mRNA of ENT1, ENT2 and CNT2 in HBECs, but no CNT2 was found in HBSMCs. The unique presence of CNT2 in endothelial cells was confirmed by the observation that mRNA of ENT1, ENT2, and CNT2 were present in rat basilar arteries but no CNT2 was detected after removal of endothelia. The mRNA expression of CNT2, but not ENT1 and ENT2, was higher in basilar arteries of spontaneously hypertensive rats and streptozotocin-induced diabetic rats compared with those in normal rats. Such increase in CNT2 in hypertension and diabetes may affect the availability of adenosine in the vicinity of adenosine receptors of endothelial cells and, thus, alter vascular functions.