Type 2 Diabetes Causes Remodeling of Cerebrovasculature via Differential Regulation of Matrix Metalloproteinases and Collagen Synthesis

Abstract

The risk of cerebrovascular disease is four-to sixfold higher in patients with diabetes. Vascular remodeling, characterized by extracellular matrix deposition and an increased media-to-lumen ratio, occurs in diabetes and contributes to the development of complications. However, diabetes-induced changes in the cerebrovascular structure remain unknown. Endothelin-1 (ET-1), a potent vasoconstrictor with profibrotic properties, is chronically elevated in diabetes. To determine diabetesmediated changes in the cerebrovasculature and the role of ET-1 in this process, type 2 diabetic GotoKakizaki (GK) rats were administered an ET A receptor antagonist for 4 weeks. Middle cerebral arteries were harvested and studies were performed to determine vascular structure. Tissue and plasma ET-1 levels were increased in GK rats compared with controls. Significant medial hypertrophy and collagen deposition resulted in an increased wall-to-lumen ratio in diabetic rats that was reduced by ET A receptor antagonism. Vascular matrix metalloproteinase (MMP)-2 activity was higher, but MMP-1 levels were significantly reduced in GK rats, and MMP levels were restored to control levels by ET A receptor antagonism. We conclude that ET-1 promotes cerebrovascular remodeling in type 2 diabetes through differential regulation of MMPs. Augmented cerebrovascular remodeling may contribute to an increased risk of stroke in diabetes, and ET A receptor antagonism may offer a novel therapeutic target. Diabetes 54:2638 -2644, 2005 T ype 2 diabetes, a disease that affects more than 17 million Americans, holds a two-to sixfold increased risk for cerebrovascular disease and stroke (1,2), and 70% of patients with a recent stroke have overt diabetes or pre-diabetes characterized by impaired fasting glucose or impaired glucose tolerance (3). However, the underlying basis of this predisposition remains unclear. Diabetic vascular complications are associated with remodeling of the vessel wall in the retinal, renal, and mesenteric circulations. However, diabetesinduced structural changes in the cerebral microvessels are unknown.The endothelium is an early target in diabetes, and dysfunction of vascular endothelial cells has a role in the diabetic vascular disease process (4). For example, the release of vasodilator and antiproliferative mediators such as nitric oxide and prostaglandin-I 2 is decreased, whereas production of endothelin-1 (ET-1) is increased (5). A significant correlation has been observed between plasma ET-1 levels and diabetes complications. In addition to being vasoconstrictive, ET-1 is also mitogenic. In streptozotocin-induced diabetes, nonselective ET receptor antagonism prevents extracellular matrix deposition in the retina as well as in the mesenteric arteries, providing evidence for a causal relationship (6,7). Nonselective blockade of ET receptors also prevents increased myogenic tone of cerebral vessels in diabetes (8), but the effect on vascular structure and the underlying mechanisms remain to be identified.The matrix metalloproteinases ...

Evidence for Vasculoprotective Effects of ETB Receptors in Resistance Artery Remodeling in Diabetes

“…Blood pressure was monitored either by telemetric method (as previously reported) (6) or via the tailcuff method (Kent Scientific, Torrington, CT), which we have previously validated on telemetry-implanted animals (5). After the spontaneous onset of diabetes, starting at 14 weeks of age, animals were divided into groups and treated for 4 weeks as follows: ET A receptor blockade, atrasentan (Abbott Labs) 5 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 in drinking water; ET B receptor blockade, A-192621 (Abbott Labs) 15 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 by oral gavage split into two daily doses; or vehicle as recommended by the manufacturer (6,16,17). Daily water consumption was measured for atrasentan treatment arm (6).…”

“…Fukuda et al (4) reported that blockade of ET-1 action inhibits aortic extracellular matrix (ECM) deposition. We showed that ET-1 levels are elevated and that an ET A antagonist prevents ECM deposition and MMP activation in middle cerebral arteries but not in the kidney of Goto-Kakizaki (GK) rats-a nonobese type 2 diabetes model (5,6). ET-1 mediates its diverse effects via distinct G protein-coupled receptor subtypes ETB AB and ETB BB .…”

“…Turnover of matrix proteins are regulated by matrix metalloproteinases (MMPs) (9). While decreased MMP activity is generally believed to contribute to ECM accumulation in diabetic kidney and in vascular tissue from patients with diabetes, we and others have recently reported that there is an early activation of MMPs in hypertension and diabetes and that ET-1 is involved in regulation of MMP activity (5,6,10,11). Recent reports indicated that MMPs are also important in generating myogenic tone of mesenteric arteries (12,13).…”

Does Bosentan Protect Diabetic Brain Alterations in Rats? The Role of Endothelin‐1 in the Diabetic Brain

“…Additionally, endothelin-1 was found to be responsible for the cerebrovascular diseases [32,33]. In previous studies, the application of endothelin-1 receptor antagonists created a cerebroprotective effect in diabetes-induced cerebrovascular dysfunction [34]. In our study, the reason why the endothelin-1 receptor antagonist was useful, particularly for the hippocampus and cerebellum, in diabetes-induced brain damage may have originated from the vasculoprotective effect.…”

Increased Cerebrovascular Sensitivity to Endothelin-1 in a Rat Model of Obstructive Sleep Apnea: A Role for Endothelin Receptor B

“…Endothelin-1 and its signaling pathways are often upregulated during pathologic states. 7,[19][20][21][22] For these studies, we used our recently developed rat model of OSA. 6 We report three major findings from this study.…”