INTEGRIN OVEREXPRESSION INDUCED BY HIGH GLUCOSE AND BY HUMAN DIABETES- POTENTIAL PATHWAY TO CELL DYSFUNCTION IN DIABETIC MICROANGIOPATHY

The nature of the process leading to the acellular nonperfused capilla ries of diabetic microangiopathy remains unknown. Because these capill aries manifest thickened basement membranes, we asked whether the proc ess causing deposition of excess extracellular matrix in diabetes modi fies cell-matrix interactions in a direction that would compromise cel l renewal. In 44 individual isolates of human umbilical vein endotheli al cells we observed that high glucose concentrations (30 mM) induce c oordinate increases in the levels of mRNAs encoding fibronectin and th e fibronectin-specific integrin receptor alpha5beta1 as well as in the cognate proteins. Expression of the integrin subunit alpha3, componen t of the alpha3beta1 polyspecific receptor for fibronectin, laminin, a nd collagen, was also up-regulated by high glucose. Overexpression of integrins correlated with increased cell attachment to exogenous fibro nectin and laminin as well as to complex matrix. Moreover, cells exhib ited firmer steady-state adhesion to their own matrix. To correlate th ese in vitro observations with events in human diabetic retinopathy we measured integrin levels in retinal trypsin digests prepared from 10 patients with 8.2 +/- 1.6 (mean +/- SE) years of diabetes and 10 age- and sex-matched nondiabetic controls. Microvessels of diabetic patient s showed increased immunostaining for beta1 integrin (P = 0.025) when compared with control microvessels. These data show that high glucose and diabetes increase integrin expression and thus alter the interacti on of vascular endothelial cells with their basement membranes in the direction of firmer cell-matrix adhesion. This could compromise the mi gration and replication critical to the reendothelialization process a nd contribute to microvascular occlusion.