Vascular ischemia is the progressive narrowing and blockage of blood vessels. The buildup of fats in the blood, known as hyperlipidemia, can increase the likelihood of a heart attack or stroke. Recent work at Temple University's School of Medicine (TUSM) found this process is regulated by caspase-1 and inhibiting this protein may stimulate new blood vessels to re-oxygenate tissue that become starved of oxygen during a period of vascular ischemia.
Diseases that develop because of vascular ischemia are the leading cause of illness in the United States. Understanding new ways to resupply tissue with oxygen that has been cutoff due to ischemia is therefore critical, writes Xiao-Feng Yang. the lead author of the study and Professor at TUSM.
"The findings describe the significance of the caspase-1 pathway to post-ischemia revascularization …," notes the scientist. "From a therapeutic point of view, we want to try to trigger revascularization and make existing vessels recover as soon as possible. The novel caspase-1 signaling pathway could have therapeutic potential in this area."
They first noted that caspase-1 works as a lipid sensor in endothelial cells, which make up a significant proportion of cells in the inner lining of the vasculature. As circulating fats increase, a complex called the caspase-1-inflammasome starts an inflammatory cascade. On top of this, caspase-1 works to inhibit endothelial cell growth, which are a major cell type that works to revascularize and maintain oxygen supply to tissue. As such, caspase-1 weakens the ability for blood vessels to recover after an ischemic stimulus has been applied.
Caspase-1 distress signals trigger different responses in cells depending on their size. They kill small endothelial cells while larger endothelial cells become activated and contribute to the high lipid-induced inflammatory response.
In further experiments they showed that by inhibiting caspase-1, the activity of an important receptor called vascular endothelial growth factor receptor-2 (VEGFR-2) is boosted--restoring the cells' homeostatic mechanism to increase vasculature formation under stress.
The models they used were on human endothelial cells, as well as a transgenic mouse model of caspase-1 deficiency, and his lab's next steps are to understand how caspase-1 regulates this in endothelial cells as well as bone marrow-derived stem cells--the latter also known to be important in vascular repair. As they've shown previously that activating caspase-1 reduces the vascular repair activity of stem cells in hyperlidemic mice--there may be important clinical application of a stem cell-based therapy for diseases caused by vascular ischemia.
- here's the release