Current research projects in the Marrelli Lab

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In this project, we seek to define how Piezo1 (a mechanosensitive ion channel) contributes to blood flow regulation in the brain. Our data indicates Piezo1 expression and function within brain endothelial cells. We have further shown that selective genetic deletion of Piezo1 in endothelium results in reduced cerebral blood flow (CBF) and that pharmacological activation of Piezo1 promotes increased CBF. We are currently exploring how loss of endothelial Piezo1 function contributes to decreased brain perfusion in mouse models of aging and amyloidosis. In addition, we are determining if selective augmentation of endothelial Piezo1 function can improve brain perfusion in these same models.

In this project, we are investigating the role of von Willebrand factor (VWF) in cerebrovascular remodeling. VWF is produced in endothelial cells and can be released from Weibel-Palade bodies into the blood as large multimers following endothelial cell activation. Release of VWF also occurs constitutively, delivering smaller multimers into the plasma and subendothelial space. While VWF is best known for its contribution to healthy hemostasis, recent data suggest that VWF may also function within the vascular wall (i.e. “intramural VWF”) to modify smooth muscle function. Our data show the presence of VWF within the vascular wall and in tight association with smooth muscle cells in both human and mouse brain vessels in aging, stroke, and amyloid-dependent pathology. We are currently examining the mechanisms by which intramural VWF promotes vascular remodeling and impaired vasomotor function of the leptomeningeal arteries/arterioles in human and mouse brain and determining if reducing intramural VWF can protect those vessels from pathological remodeling and impaired function.

In this project, we are using ‘non-pungent’ TRPV1 channel agonists (capsinoids) to promote therapeutic hypothermia following ischemic stroke. We have shown that delivery of these agonists promotes mild hypothermia (core body temp 33-35 °C) in mice. We have also shown that capsinoid-induced hypothermia produced in the post-stroke period lessens stroke injury and improves functional recovery.