Increased hemorrhagic transformation and altered infarct size and localization after experimental stroke in a rat model type 2 diabetes

Abstract

Background: Interruption of flow through of cerebral blood vessels results in acute ischemic stroke. Subsequent breakdown of the blood brain barrier increases cerebral injury by the development of vasogenic edema and secondary hemorrhage known as hemorrhagic transformation (HT). Diabetes is a risk factor for stroke as well as poor outcome of stroke. The current study tested the hypothesis that diabetes-induced changes in the cerebral vasculature increase the risk of HT and augment ischemic injury.

Methods: Diabetic Goto-Kakizaki (GK) or control rats underwent 3 hours of middle cerebral artery occlusion and 21 h reperfusion followed by evaluation of infarct size, hemorrhage and neurological outcome.

Results: Infarct size was significantly smaller in GK rats (10 +/- 2 vs 30 +/- 4%, p < 0.001). There was significantly more frequent hematoma formation in the ischemic hemisphere in GK rats as opposed to controls. Cerebrovascular tortuosity index was increased in the GK model (1.13 +/- 0.01 vs 1.34 +/- 0.06, P < 0.001) indicative of changes in vessel architecture.

Conclusion: These findings provide evidence that there is cerebrovascular remodeling in diabetes. While diabetes-induced remodeling appears to prevent infarct expansion, these changes in blood vessels increase the risk for HT possibly exacerbating neurovascular damage due to cerebral ischemia/reperfusion in diabetes.

Figure 1

Infarct size is reduced in diabetes. (A) A representative image showing TTC staining for infarct size and localization in control Wistar (n = 10) and diabetic GK rats (n = 9). (B) Bar graph depicting infarct size in all the animals. Results are given mean ± sem and *p < 0.05 vs control.

Figure 2

Incidence of HT is increased in diabetes. (A) A representative image showing visible hemorrhage in control Wistar (n = 10) and diabetic GK rats (n = 9). (B) Bar graph depicting incidence of HT in all the animals. Results are given mean ± sem and *p < 0.05 vs control.

Figure 3

Increased tortuosity as index of vascular remodeling in diabetes. (A) A representative image showing superficial cerebral vessels in control Wistar (n = 5) and diabetic GK rats (n = 4), and (B) Bar graph summarizing results of TI measurements in all the animals. Results are given mean ± sem and *p < 0.05 vs control.

Figure 4

Increased MMP activity in diabetes. (A) Vessel segments were analyzed for morphological changes and collagen deposition by Masson staining which did not show any difference between control and diabetes groups. (B) A representative zymogram showing changes in vascular MMP-2 activity and densitometric analysis of lytic bands from all samples indicates an increase in MMP-2 activity. Results are given mean ± sem (n = 5–9) and *p < 0.05 vs control.