Vascular Protection in Diabetic Stroke: Role of Matrix Metalloprotease-Dependent Vascular Remodeling

Abstract

Temporary focal ischemia causes greater hemorrhagic transformation (HT) in diabetic Goto-Kakizaki (GK) rats, a model with increased cerebrovascular matrix metalloprotease (MMP) activity and tortuosity. The objective of the current study was to test the hypotheses that (1) diabetes-induced cerebrovascular remodeling is MMP dependent and (2) prevention of vascular remodeling by glucose control or MMP inhibition reduces HT in diabetic stroke. Control and GK rats were treated with vehicle, metformin, or minocycline for 4 weeks, and indices of remodeling including vascular tortuosity index, lumen diameter, number of collaterals, and middle cerebral artery (MCA) MMP activity were measured. Additional animals were subjected to 3 hours MCA occlusion/21 hours reperfusion, and infarct size and HT were evaluated as indices of neurovascular injury. All remodeling markers including MMP-9 activity were increased in diabetes. Infarct size was smaller in minocycline-treated animals. Both metformin and minocycline reduced vascular remodeling and severity of HT in diabetes. These results provide evidence that diabetes-mediated stimulation of MMP-9 activity promotes cerebrovascular remodeling, which contributes to greater HT in diabetes. Metformin and minocycline offer vascular protection, which has important clinical implications for diabetes patients who are at a fourfold to sixfold higher risk for stroke.

Metformin ameliorates BSCB disruption by inhibiting neutrophil infiltration and MMP‐9 expression but not direct TJ proteins expression regulation

“…A study in skin tissue showed that metformin significantly inhibits MMP‐9 expression and protect collagen degradation from solar ultra‐violet radiation 50. It is also reported that metformin could reduce vascular remodelling and severity of haemorrhagic transformation by inhibiting MMP‐9 activity 51. Therefore, we investigated the level of MMP‐9 after metformin administration in SCI rats, our data demonstrated that metformin could down‐regulate MMP‐9 significantly, which contributed to decrease degradation of TJ proteins following SCI.…”

Cerebral Myogenic Reactivity and Blood Flow in Type 2 Diabetic Rats: Role of Peroxynitrite in Hypoxia-Mediated Loss of Myogenic Tone

“…These data are in agreement with previous observations that vasomotor dysfunction in diabetes precedes the advent of structural pathologies (Bagi et al, 2004;Oizumi et al, 2006). We also reported that metformin treatment started at the onset of diabetes prevents increased myogenic tone in this model, suggesting that hyperglycemia mediates this effect (Elgebaly et al, 2010). Diabetic BBZDR/ Wor rats used in the study by Jarajapu et al (2008) had glucose levels in excess of 400 mg/dl; however, PCAs isolated from in these animals exhibited increased tone after 4 weeks of diabetes resulting from increased phospholipase C activation.…”

Cerebral Neovascularization in Diabetes: Implications for Stroke Recovery and beyond

“…It is also of great interest that in both type 1 and type 2 diabetes models, in which repair and recovery are impaired, there is increased bleeding into the brain after ischemic stroke. [101][102][103][104][105] However, the impact of bleeding on vascular repair has not been fully studied. Evidence from intracranial hemorrhage models suggests that hemoglobin and heme released from red blood cells enter the brain parenchyma and free iron from further degradation of the heme molecule, disrupts cellular integrity and function via increased oxidative stress.…”

“…112 In other studies where immature vessel formation was observed, 104,105 authors reported increased Ang-2 and decreased Ang-1 expression in the brain sections of diabetic rats. 103,104 V. Clinical Relevance On the basis of experimental evidence, cerebral neovascularization response differs in diabetes, stroke, and diabetic stroke ( Figure 6). Important questions remain unresolved with respect to the clinical relevance of these studies: (1) How can we promote adaptive brain neovascularization in health and disease?…”

“…Ultimately, animals exhibit poor functional outcome. [101][102][103] To determine the impact of diabetes on cerebral neovascularization after an ischemic event, we compared and contrasted various indices of cerebral neovascularization in the ipsilateral ischemic and contralateral hemispheres of control and diabetic rats subjected to sham or stroke surgery. Several important observations were made.…”