Endothelin-1-mediated cerebrovascular remodeling is not associated with increased ischemic brain injury in diabetesThis article is one of a selection of papers published in the two-part special issue entitled 20 Years of Endothelin Research.

Abstract

Diabetes increases the risk as well as the poor outcome of stroke. Matrix metalloprotease (MMP) activation disrupts blood-brain barrier integrity after cerebral ischemia. We have previously shown that type 2 diabetes promotes remodeling of middle cerebral arteries (MCA) characterized by increased media:lumen (M/L) ratio and MMP activity in an endothelin (ET)-1-dependent manner in the Goto-Kakizaki (GK) rat model. In the present study, we examined the effects of ET-1-mediated vascular remodeling on neurovascular damage following cerebral ischemic injury in GK rats 5 and 12 weeks after the onset of diabetes. The MCA structure, cerebral perfusion as well as infarct size, and hemorrhage were measured in control and diabetic rats subjected to transient MCA occlusion. M/L ratio was increased after 12 but not 5 weeks of diabetes. The baseline cerebral perfusion was lower and the infarct volume was smaller in diabetic rats at both age groups. The incidence of hemorrhagic transformation was higher after 5 weeks of diabetes as compared 12 weeks or the control groups. These findings provide evidence that ET-1 mediated cerebrovascular remodeling does not worsen the neurovascular damage of ischemic brain injury in diabetes. It is possible that this early remodeling response is compensatory in nature to regulate vascular tone and integrity especially when ischemia is layered on diabetic vascular disease.

Dual endothelin receptor antagonism with bosentan reverses established vascular remodeling and dysfunctional angiogenesis in diabetic rats: Relevance to glycemic control

“…The vascular remodeling was associated with impaired myogenic reactivity and decreased cerebral blood flow (Kelly-Cobbs et al, 2011b). Our results also showed that hyperglycemia-mediated upregulation of the ET system plays a critical role in the development of vascular remodeling where glycemic control or dual ET-1 antagonism prevented diabetes-induced remodeling (Kelly-Cobbs et al, 2011a, Kelly-Cobbs, Harris, 2011b, Li, Kelly-Cobbs, 2010, Sachidanandam et al, 2009a). Accordingly, the first goal of this study was to determine whether and to what extent this remodeling continues to progress and whether it can be reversed if treatment is started late in the disease.…”

“…Within the cerebrovasculature, this remodeling was associated with impaired myogenic reactivity, decreased tone, and decrease in cerebral blood flow (Kelly-Cobbs, Elgebaly, 2011a). We have recently showed that glycemic control with metformin or dual receptor antagonism by bosentan can prevent large artery remodeling and improves myogenic function (Li, Kelly-Cobbs, 2010, Sachidanandam et al, 2008, Sachidanandam, Hutchinson, 2009a, Sachidanandam et al, 2009b, Sachidanandam, Portik-Dobos, 2010). While these results provided important information with regard to use of these agents for preventive strategies in diabetes, the therapeutic potential remained undefined and the current study now provides evidence that established pathological remodeling in diabetes can be at least partially reversed by these approaches.…”

“…Our studies in Goto-Kakizaki rats, a lean type II diabetes animal model, have illustrated a crucial involvement of the endothelin (ET-1) system in diabetes-induced cerebrovascular remodeling (Li et al, 2010). We showed that diabetes caused hypertrophic remodeling of middle cerebral arteries (MCA) with increased wall thickness and wall to lumen ratio as the disease progresses (Harris et al, 2005).…”

Vasotrophic Regulation of Age-Dependent Hypoxic Cerebrovascular Remodeling

“…ET appears involved in hypertension-induced hypertrophy of cerebral arteries without changing their distensibility [240]. Diabetic mice can also display increased ET receptor levels and ET-1 dependent matrix metalloproteinase activation, which can facilitate cerebrovascular remodeling, especially after hypoxic exposure [241, 242]. Through binding to ETA receptor, increased ET levels can activate the transcription factor Nuclear Factor of Activated T cells, isoform 3 (NFAT3), resulting in hypertension and vascular remodeling.…”

Cognition and Hemodynamics

“…In contrast, neovascularization in the brain may be augmented yet still dysfunctional [107]. This condition manifests as an increased media-lumen ratio, a compromised BBB and increased activity of matrix mattaloproteinases (MMP) [108]. Therefore, inflammation- activated microglial cells and invading macrophages play important roles in altered neurovascular coupling, BBB permeability and, ultimately, neuronal loss.…”