Vascular Injury and Recovery in Diabetic Ischemic Stroke

糖尿病增加了中风的风险，并增加了包括身体残疾和中风后的后果。 认知障碍（PSCI）。糖尿病患者更容易出血进入大脑（出血性 转化，HT），缺血性中风的一个重要并发症，这是在女性研究很少。缺乏 了解出血增加如何发生并影响恢复和再生过程 神经血管网络内的血管紧张素II阻碍了中风恢复的新治疗策略的发展。 虽然临床上已知女性遭受更差的结果和PSCI，需要长期 护理，雌性动物纳入不足，加上糖尿病模型的使用有限， 临床前中风研究进一步加深了这一差距。我们的目标是填补这一巨大的知识空白 通过关注糖尿病女性中HT增加的机制和后果。我们创作了这部小说 观察结果：1）年轻的糖尿病雌性大鼠失去了通常在对照雌性大鼠中看到的神经保护作用 动物和发展更大的HT比对照组，甚至糖尿病雄性大鼠; 2）基质金属蛋白酶 （MMP）-3，一种已知引起HT并受Toll样受体4（TLR 4）调节的酶，增加至约100 μ g/ml。 雌性糖尿病大鼠脑微血管病变程度更大; 3）雄性糖尿病动物脑微血管病变程度更大， 恢复期多细胞死亡途径激活导致的血管损失，女性糖尿病患者 动物则不然，而是经历类似于内皮细胞的内皮细胞表型变化- 间充质转化，EndMT，一个与瘢痕形成和愈合受损相关的过程，和4）在长期- 长期来看，糖尿病影响男女感觉运动和认知能力的恢复。因此，我们假设， 内皮（e）TLR 4在放大的血管损伤和受损的血管修复中具有双重作用， 女性糖尿病患者的恢复：eTLR 4介导的MMP 3活性增加放大HT， 维持TLR 4活化，导致转化生长因子（TGF）-β促进的EndMT → 神经血管单位（NVU）完整性→功能恢复不良。3个目标将测试以下子假设：1） eTLR 4介导的MMP 3激活放大了糖尿病患者的HT和卒中结局; 2）持续的eTLR 4 由于HT介导的EndMT的激活导致糖尿病中NVU完整性的丧失和不良恢复;以及3） 放大的TGF-β信号传导是糖尿病中eTLR 4驱动的EndMT的潜在机制。9翻译 和机制研究超过5年，并利用严格的行为评估控制和糖尿病 雌性动物，药理学和遗传操作在体内和体外，我们将推进我们的 了解女性（缺血性卒中研究不足的人群）的卒中恢复，并确定 EndMT预防作为一种新的有前途的治疗策略，不仅适用于卒中，而且适用于血管贡献 认知障碍和痴呆（VCID）疾病谱，其中包括PSCI。

Diabetes increases the risk for stroke and worsens outcomes including physical disability and post-stroke cognitive impairment (PSCI). Diabetic patients are more likely to bleed into the brain (hemorrhagic transformation, HT), an important complication of ischemic stroke, that is poorly studied in females. The lack of understanding on how increased bleeding occurs and influences the restorative and regenerative processes within the neurovascular networks hindered the development of new therapeutic strategies for stroke recovery. While clinically it is known that women suffer more from poor outcomes and PSCI, necessitating long-term nursing care, the inadequate inclusion of female animals coupled with the limited use of diabetic models in preclinical stroke research has further deepened this gap. Our objective is to address this vast knowledge gap by focusing on the mechanisms and consequences of increased HT in diabetic females. We made the novel observations that: 1) young diabetic female rats lose the neuroprotection typically seen in control female animals and develop greater HT than in controls and even diabetic male rats; 2) matrix metalloprotease (MMP)-3, an enzyme known to cause HT and to be regulated by toll like receptor 4 (TLR4), is increased to a greater degree in cerebral microvessels of female diabetic rats; 3) while male diabetic animals show significant loss of cerebrovasculature by activation of multiple cell death pathways in the recovery period, female diabetic animals do not, but rather undergo phenotypic changes in endothelial cells resembling endothelial- mesenchymal transition, EndMT, a process associated with scarring and impaired healing, and 4) in the long- term, diabetes worsens sensorimotor and cognitive recovery in both sexes. Thus, we hypothesize that endothelial (e)TLR4 has a dual role in amplified vascular injury and compromised vascular restoration & recovery in females with diabetes: eTLR4-mediated increase in MMP3 activity amplifies HT which in turn sustains TLR4 activation leading to transforming growth factor (TGF)-β-facilitated EndMT → loss of neurovascular unit (NVU) integrity → poor functional recovery. 3 aims will test the subhypotheses that: 1) eTLR4-mediated MMP3 activation amplifies HT and worsens stroke outcomes in diabetes; 2) sustained eTLR4 activation due to HT mediates EndMT resulting in loss of NVU integrity and poor recovery in diabetes; and 3) amplified TGF-β signaling is the underlying mechanism of eTLR4-driven EndMT in diabetes. In 9 translational and mechanistic studies over 5 years, and utilizing rigorous behavioral assessment of control and diabetic female animals, pharmacologic and genetic manipulations in vivo and in vitro, we will advance our understanding of stroke recovery in females, an understudied population in ischemic stroke, and identify EndMT prevention as a new promising therapeutic tactic for not only stroke but also for vascular contributions to cognitive impairment and dementia (VCID) spectrum of diseases which include PSCI.