Endothelium- targeted overexpression of Krüppel- like factor 11 protects the blood- brain barrier function after ischemic brain injury

Microvascular endothelial cell (EC) injury and the subsequent blood- brain barrier (BBB) breakdown are frequently seen in many neurological disorders, including stroke. We have previously documented that peroxisome proliferator- activated receptor gamma (PPARγ)- mediated cerebral protection during ischemic insults needs Krüppel- like factor 11 (KLF11) as a critical coactivator. However, the role of endothelial KLF11 in cerebrovascular function and stroke outcome is unclear. This study is aimed at investigating the regulatory role of endothelial KLF11 in BBB preservation and neurovascular protection after ischemic stroke. EC- targeted overexpression of KLF11 significantly mitigated BBB leakage in ischemic brains, evidenced by significantly reduced extravasation of BBB tracers and infiltration of peripheral immune cells, and less brain water content. Endothelial cell- selective KLF11 transgenic (EC- KLF11 Tg) mice also exhibited smaller brain infarct and improved neurological function in response to ischemic insults. Furthermore, EC- targeted transgenic overexpression of KLF11 preserved cerebral tight junction (TJ) levels and attenuated the expression of pro- inflammatory factors in mice after ischemic stroke. Mechanistically, we demonstrated that KLF11 directly binds to the promoter of major endothelial TJ proteins including occludin and ZO- 1 to promote their activities. Our data indicate that KLF11 functions at the EC level to preserve BBB structural and functional integrity, and therefore, confers brain protection in ischemic stroke. KLF11 may be a novel therapeutic target for the treatment of ischemic stroke and other neurological conditions involving BBB breakdown and neuroinflammation.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/155919/1/bpa12831_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155919/2/bpa12831.pd

More than 10,000 pre-Columbian earthworks are still hidden throughout Amazonia

Indigenous societies are known to have occupied the Amazon basin for more than 12,000 years, but the scale of their influence on Amazonian forests remains uncertain. We report the discovery, using LIDAR (light detection and ranging) information from across the basin, of 24 previously undetected pre-Columbian earthworks beneath the forest canopy. Modeled distribution and abundance of large-scale archaeological sites across Amazonia suggest that between 10,272 and 23,648 sites remain to be discovered and that most will be found in the southwest. We also identified 53 domesticated tree species significantly associated with earthwork occurrence probability, likely suggesting past management practices. Closed-canopy forests across Amazonia are likely to contain thousands of undiscovered archaeological sites around which pre-Columbian societies actively modified forests, a discovery that opens opportunities for better understanding the magnitude of ancient human influence on Amazonia and its current state

Long Non-Coding RNA Malat1 Regulates Angiogenesis in Hindlimb Ischemia

Angiogenesis is a complex process that depends on the delicate regulation of gene expression. Dysregulation of transcription during angiogenesis often leads to various human diseases. Emerging evidence has recently begun to show that long non-coding RNAs (lncRNAs) may mediate angiogenesis in both physiological and pathological conditions; concurrently, underlying molecular mechanisms are largely unexplored. Previously, our lab identified metastasis associates lung adenocarcinoma transcript 1 (Malat1) as an oxygen-glucose deprivation (OGD)-responsive endothelial lncRNA. Here we reported that genetic deficiency of Malat1 leads to reduced blood vessel formation and local blood flow perfusion in mouse hind limbs at one to four weeks after hindlimb ischemia. Malat1 and vascular endothelial growth factor receptor 2 (VEGFR2) levels were found to be increased in both cultured mouse primary skeletal muscle microvascular endothelial cells (SMMECs) after 16 h OGD followed by 24 h reperfusion and in mouse gastrocnemius muscle that underwent hindlimb ischemia followed by 28 days of reperfusion. Moreover, Malat1 silencing by locked nucleic acid (LNA)-GapmeRs significantly reduced tube formation, cell migration, and cell proliferation in SMMEC cultures. Mechanistically, RNA subcellular isolation and RNA-immunoprecipitation experiments demonstrate that Malat1 directly targets VEGFR2 to facilitate angiogenesis. The results suggest that Malat1 regulates cell-autonomous angiogenesis through direct regulation of VEGFR2

MMP-3 Knockout Induces Global Transcriptional Changes and Reduces Cerebral Infarction in Both Male and Female Models of Ischemic Stroke

Ischemic stroke followed by reperfusion (IR) leads to extensive cerebrovascular injury characterized by neuroinflammation and brain cell death. Inhibition of matrix metalloproteinase-3 (MMP-3) emerges as a promising therapeutic approach to mitigate IR-induced stroke injury. We employed middle cerebral artery occlusion with subsequent reperfusion (MCAO/R) to model ischemic stroke in adult mice. Specifically, we investigated the impact of MMP-3 knockout (KO) on stroke pathophysiology using RNA sequencing (RNA-seq) of stroke brains harvested 48 h post-MCAO. MMP-3 KO significantly reduced brain infarct size following stroke. Notably, RNA-seq analysis showed that MMP-3 KO altered expression of 333 genes (252 downregulated) in male stroke brains and 3768 genes (889 downregulated) in female stroke brains. Functional pathway analysis revealed that inflammation, integrin cell surface signaling, endothelial- and epithelial-mesenchymal transition (EndMT/EMT), and apoptosis gene signatures were decreased in MMP-3 KO stroke brains. Intriguingly, MMP-3 KO downregulated gene signatures more profoundly in females than in males, as indicated by greater negative enrichment scores. Our study underscores MMP-3 inhibition as a promising therapeutic strategy, impacting multiple cellular pathways following stroke

Vascular Smooth Muscle Cells in Aortic Aneurysm: From Genetics to Mechanisms

Aortic aneurysm, including thoracic aortic aneurysm and abdominal aortic aneurysm, is the second most prevalent aortic disease following atherosclerosis, representing the ninth‐leading cause of death globally. Open surgery and endovascular procedures are the major treatments for aortic aneurysm. Typically, thoracic aortic aneurysm has a more robust genetic background than abdominal aortic aneurysm. Abdominal aortic aneurysm shares many features with thoracic aortic aneurysm, including loss of vascular smooth muscle cells (VSMCs), extracellular matrix degradation and inflammation. Although there are limitations to perfectly recapitulating all features of human aortic aneurysm, experimental models provide valuable tools to understand the molecular mechanisms and test novel therapies before human clinical trials. Among the cell types involved in aortic aneurysm development, VSMC dysfunction correlates with loss of aortic wall structural integrity. Here, we discuss the role of VSMCs in aortic aneurysm development. The loss of VSMCs, VSMC phenotypic switching, secretion of inflammatory cytokines, increased matrix metalloproteinase activity, elevated reactive oxygen species, defective autophagy, and increased senescence contribute to aortic aneurysm development. Further studies on aortic aneurysm pathogenesis and elucidation of the underlying signaling pathways are necessary to identify more novel targets for treating this prevalent and clinical impactful disease

Capillary flow in sacrificially etched nanochannels

Planar nanochannels are fabricated using sacrificial etching technology with sacrificial cores consisting of aluminum, chromium, and germanium, with heights ranging from 18 to 98 nm. Transient filling via capillary action is compared against the Washburn equation [E. W. Washburn, Phys. Rev. 17, 273 (1921)], showing experimental filling speeds significantly lower than classical continuum theory predicts. Departure from theory is expressed in terms of a varying dynamic contact angle, reaching values as high as 83° in channels with heights of 18 nm. The dynamic contact angle varies significantly from the macroscopic contact angle and increases with decreasing channel dimensions

Genetic ablation of diabetes-associated gene Ccdc92 reduces obesity and insulin resistance in mice

Summary: Multiple genome-wide association studies (GWAS) have identified specific genetic variants in the coiled-coil domain containing 92 (CCDC92) locus that is associated with obesity and type 2 diabetes in humans. However, the biological function of CCDC92 in obesity and insulin resistance remains to be explored. Utilizing wild-type (WT) and Ccdc92 whole-body knockout (KO) mice, we found that Ccdc92 KO reduced obesity and increased insulin sensitivity under high-fat diet (HFD) conditions. Ccdc92 KO inhibited macrophage infiltration and fibrosis in white adipose tissue (WAT), suggesting Ccdc92 ablation protects against adipose tissue dysfunction. Ccdc92 deletion also increased energy expenditure and further attenuated hepatic steatosis in mice on an HFD. Ccdc92 KO significantly inhibited the inflammatory response and suppressed the NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome in WAT. Altogether, we demonstrated the critical role of CCDC92 in metabolism, constituting a potential target for treating obesity and insulin resistance

Endothelium‐targeted overexpression of Krüppel‐like factor 11 protects the blood‐brain barrier function after ischemic brain injury

Microvascular endothelial cell (EC) injury and the subsequent blood- brain barrier (BBB) breakdown are frequently seen in many neurological disorders, including stroke. We have previously documented that peroxisome proliferator- activated receptor gamma (PPARγ)- mediated cerebral protection during ischemic insults needs Krüppel- like factor 11 (KLF11) as a critical coactivator. However, the role of endothelial KLF11 in cerebrovascular function and stroke outcome is unclear. This study is aimed at investigating the regulatory role of endothelial KLF11 in BBB preservation and neurovascular protection after ischemic stroke. EC- targeted overexpression of KLF11 significantly mitigated BBB leakage in ischemic brains, evidenced by significantly reduced extravasation of BBB tracers and infiltration of peripheral immune cells, and less brain water content. Endothelial cell- selective KLF11 transgenic (EC- KLF11 Tg) mice also exhibited smaller brain infarct and improved neurological function in response to ischemic insults. Furthermore, EC- targeted transgenic overexpression of KLF11 preserved cerebral tight junction (TJ) levels and attenuated the expression of pro- inflammatory factors in mice after ischemic stroke. Mechanistically, we demonstrated that KLF11 directly binds to the promoter of major endothelial TJ proteins including occludin and ZO- 1 to promote their activities. Our data indicate that KLF11 functions at the EC level to preserve BBB structural and functional integrity, and therefore, confers brain protection in ischemic stroke. KLF11 may be a novel therapeutic target for the treatment of ischemic stroke and other neurological conditions involving BBB breakdown and neuroinflammation.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/155919/1/bpa12831_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155919/2/bpa12831.pd