Abstract 108: Stroke Amplifies Cerebrovascular Matrix Metalloproteinase-3 (MMP3) Activity In Diabetes: Potential Sex Differences And Impact On Endothelial To Mesenchymal Transition (EndMT)

Abstract

Both female sex and diabetes increase the risk of poor stroke recovery, but underlying mechanisms are unclear. We reported that inhibition of MMP3 with UK356618 prevents hemorrhagic transformation (HT) in male diabetic rats, and female diabetic rats develop greater HT than males. Emerging evidence suggests that MMP3 may contribute to the regulation of EndMT, a process associated with scarring and impaired healing. We tested the hypotheses that: 1) MMP3 activity is amplified to a greater extent in the cerebrovasculature of female diabetic rats, especially after stroke; 2) EndMT occurs in female brain endothelial cells (BMVECs), and 3) MMP3 inhibition in stroke and diabetes-like conditions improves cell integrity/survival in female BMVECs. Methods: Cerebral microvascular homogenates were prepared from control and diabetic male and female rats subjected to sham or 60-min middle cerebral artery occlusion. MMP3 expression/activity was measured. EndMT /endothelial integrity were assessed by immunoblotting in male and female BMVECs cultured in normal, diabetes or ischemia-like conditions. Results (Table): Cerebrovascular MMP3 expression/activity is higher in females. TGF-β, a major EndMT inducer, significantly decreased VE-Cadherin and increased EndMT markers αSMA and p-SMAD2 to a greater extent in female cells. Ongoing studies suggested that MMP3 inhibitor UK356618 improved the expression of tight junction protein occludin and cell survival, which was associated with a decrease in transforming growth factor receptor-1 (TGFβR1). Conclusions: The impact of long-term MMP3 inhibition on EndMT, neurovascular restoration, and post-stroke recovery in females and diabetes needs to be further explored.