Vascular Injury and Recovery in Diabetic Ischemic Stroke

糖尿病增加了中风的风险，并恶化了结果，包括身体残疾和中风后 认知障碍(PSCI)。糖尿病患者更有可能出血进入大脑(出血性 转化)，这是缺血性中风的一个重要并发症，在女性中研究较少。缺乏 了解出血增加是如何发生并影响恢复和再生过程的 神经血管内网络阻碍了中风康复新治疗策略的发展。 虽然在临床上已经知道，妇女更多地遭受不良结局和PSCI的痛苦，需要长期的 护理，包括雌性动物的不足，加上糖尿病模型的有限使用 临床前卒中研究进一步加深了这一差距。我们的目标是解决这一巨大的知识鸿沟 通过重点研究糖尿病女性羟色胺升高的机制和后果。我们写了这部小说 观察到：1)年轻的糖尿病雌性大鼠失去了对照组雌性大鼠典型的神经保护 与对照组甚至糖尿病雄性大鼠相比，动物的甲状旁腺素水平更高；2)基质金属蛋白酶 (基质金属蛋白酶)-3，一种已知引起高血压的酶，由Toll样受体4(TLR4)调节，增加到 雌性糖尿病大鼠脑微血管病变程度较大；3)雄性糖尿病大鼠脑微血管病变明显 女性糖尿病患者恢复期多条细胞死亡通路激活导致脑血管功能丧失 动物不会，而是经历内皮细胞的表型变化，类似内皮细胞- 间充质转化，EndMT，一种与瘢痕形成和愈合受损相关的过程，以及4)在长期- 总而言之，无论男女，糖尿病都会恶化感觉运动和认知恢复。因此，我们假设 内皮(E)TLR4在放大的血管损伤和受损的血管修复中具有双重作用 女性糖尿病患者的康复：eTLR4介导的MMP3活性增加增强了羟色胺，进而 维持TLR4激活导致转化生长因子-β促进的EndMT→丢失 神经血管单位(NVU)完整性、→功能恢复差。3 AIMS将检验以下假设：1) ETLR4介导的MMP3激活放大高血压并恶化糖尿病患者的中风预后；2)持续的eTLR4 羟色胺激活介导EndMT，导致糖尿病患者NVU完整性丧失和恢复不良；以及3) 被放大的转化生长因子-β信号是eTLR4在糖尿病中驱动EndMT的潜在机制。在9个翻译版本中 和超过5年的机制研究，并利用严格的控制和糖尿病行为评估 雌性动物，体内和体外的药理和遗传操作，我们将推进我们的 了解女性的中风康复情况，这是一个在缺血性中风中研究不足的人群，并确定 EndMT预防不仅对卒中而且对血管贡献是一种有前途的新治疗策略 到认知损害和痴呆(VCID)的疾病谱，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.