Regulation of leptomeningeal collaterals by the endothelial mechanosensor, Piezo1
Description: Ischemic stroke affects approximately 800,000 people in the U.S. each year, making it a top public health concern. The severity of stroke or amenability to treatment is significantly dependent on the presence of functional leptomeningeal collateral vessels (LMCs). LMCs are vascular redundancies that offer alternative routes of perfusion from pre-existing vascular pathways. Collaterals allow for blood flow to reach a target tissue when a primary conduit is blocked. The extent of collateral circulation positively correlates with good outcome following ischemic stroke in experimental stroke models and human stroke patients. In addition, treatment effectiveness also positively correlates with collateral status. Unfortunately, collateral vessels, and thus the perfusion capacity, decrease in number and diameter ("rarefaction") with aging. Piezo1 is a mechano-sensitive calcium-permeable ion channel that has recently been implicated in flow-mediated regulation of vascular diameter of peripheral arteries. Piezo1 is proposed to mediate both acute vasodilation to increased blood flow (i.e. via increased vascular shear forces) as well as chronic vascular remodeling in response to sustained increased blood flow. The endothelium appears to be a critical site of Piezo1 action, as hemizygous endothelial-specific deletion of Piezo1 results in defective endothelial cell alignment in arteries while homozygous deletion results in more severe vascular defects and embryonic lethality. However, the role of Piezo1 in regulating cerebral blood flow or cerebrovascular tone is currently unknown. We hypothesize that endothelial Piezo1 contributes to 1) acute regulation of collateral vessel diameter in response to increased flow, 2) chronic maintenance of collaterals during natural aging (by opposing collateral rarefaction), and 3) promotion of collateral remodeling after stroke. We will employ inducible EC-specific Piezo1 knockout mice (Piezo1iecKO), Piezo1 reporter mice, and EC-specific calcium indicator mice (ECGCamp6s). We will test our hypotheses using a combination of isolated vessel preparations and intravital preparations in young and aged mice.
Funder: American Heart Association
Amount: $131,400
Funding type: fellowship
Funder scheme: Postdoctoral Fellowship
Start date: 2020-01-01
End date: 2020-11-30
Investigators: Monica Goss, Monica Goss
Institution: The University of Texas Health Science Center at Houston
Funded outputs count: 1
Funder award ID: 20POST35180054
OpenAlex ID: G944731075