The type 2 diabetic db/db mouse experiences vascular dysfunction typified by changes in the contraction and relaxation profiles of small mesenteric arteries (SMA). Contractions of SMA from the db/db mouse to phenylephrine (PE) were significantly enhanced and acetylcholine (ACh)-induced relaxations were significantly depressed. Drug treatment of db/db mice with a non-thiazolidinedione PPAR- agonist and insulin sensitizing agent 2-(2-(4-phenoxy-2-propylphenoxy) ethyl)indole-5-acetic acid (COOH) completely prevented the changes in endothelium-dependent relaxation, but, with discontinuation of therapy, endothelial dysfunction returned. The dysfunctional SMA were found to specifically up regulate the expression of a 35kDa isoform of the tail-anchored sarcolemmal membrane associated protein (SLMAP), which is a component of the cells mitotic organizing centre as well as the excitation-contraction coupling apparatus in muscle cells. Real-time PCR revealed high SLMAP mRNA level in the db/db microvasculature, which was markedly down regulated during COOH treatment but elevated again when drug therapy was discontinued. These data reveal that the microvasculature in db/db mice undergoes significant changes in vascular function with the endothelial component of vascular dysfunction specifically correlating with the over expression of SLMAP. Thus changes in SLMAP expression may be an important indicator for microvascular disease associated with type 2 diabetes.