HB-EGF/EGFR signaling in capillary dysfunction in CADASIL
Awardee: Masayo Koide
Institution: University of Vermont Larner College of Medicine
Award Amount: $82,795
Funding Period: February 1, 2021 - January 31, 2022
Summary:
CADASIL, short for Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarct and Leukoencephalopathy, is the most common genetic cause of a pathology known as small vessel disease (SVD) of the brain. During SVDs such as CADASIL, the structure and function of small blood vessels (arteries, arterioles, venules, and capillaries) within the brain become compromised. An early result of this vascular dysfunction is a decrease in blood flow to the brain (cerebral blood flow or CBF), which eventually leads to dementia and/or strokes. This study will elucidate the molecular mechanisms of compromised CBF increases in response to neural activity (“functional hyperemia”) using a clinically relevant CADASIL mouse model. We will specifically focus on examining the impact of CADASIL on capillaries, the smallest and most abundant vessels in the brain, which we have previously shown to be the molecular cornerstone in functional hyperemia responses in healthy animals. Considering that it is known that CADASIL causes an abnormal accumulation of specific proteins around the outside of small vessels in the brain, we propose to examine how two of these proteins, epidermal growth factor receptor (EGFR) and heparin-binding EGF-like growth factor (HB-EGF), contribute to capillary dysfunction in CADASIL. This project, by providing a greater understanding of the cellular pathways contributing to CADASIL pathologies, will create a firm footing for future therapeutic development.
Publications:
Final Report Lay Summary:
CADASIL, short for Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarct and Leukoencephalopathy, is the most common genetic cause of a pathology known as smal vessel disease (SVD) of the brain. During SVDs such as CADASIL, the structure and function of smal blood vessels (arteries, arterioles, venules, and capilaries) within the brain become compromised. An early result of this vascular dysfunction is a decrease in blood flow to the brain (cerebral blood flow or CBF), which eventua ly leads to dementia and/or strokes. This study examined the molecular mechanisms of compromised CBF increases in response to neural activity (“functional hyperemia”) using a clinica ly relevant CADASIL mouse model. We specifica ly focused on examining the impact of CADASIL on capilaries, the sma lest and most abundant vessels in the brain, which we have previously shown to be the molecular cornerstone in functional hyperemia responses in healthy animals. Considering that it is known that CADASIL causes an abnormal accumulation of specific proteins around the outside of sma l vessels in the brain, we examined how two of these proteins, epidermal growth factor receptor (EGFR) and heparin-binding EGF-like growth factor (HBEGF), contribute to capilary dysfunction in CADASIL. State-of-art techniques, including laser Doppler flowmetry, patch-clamp electrophysiology, two-photon microscopy and a newly developed capilary-arteriole continuum preparation were used to examine the role of capilary EGFR signaling in causing cerebral blood flow deficits in CADASIL model mice. Notably, we found that CADASIL-induced functional hyperemia deficits were caused by insufficient phosphatidylinositol 4,5-bisphosphate (PIP2), an endogenous activator of Kir2.1 potassium channels in capilary EC membranes. Furthermore, our data demonstrates that PIP2 content in capilary EC membranes can be modified by HB-EGF/EGFR signaling. In fact, the application of PIP2 or stimulation of EGFR restored capilary Kir2.1 channel activity and functional hyperemia in CADASIL mice. These results support the concept that HB-EGF/EGFR signaling modulates PIP2 content in capilary EC membrane, EC Kir2.1 channel activity, and functional hyperemia. In summary, we demonstrated a novel mechanism underlying functional hyperemia deficits in CADASIL. Our findings suggest that capilary HB-EGF/EGFR signaling and exogenous PIP2 administration may have potential as therapeutic targets as CADASIL treatments. This project, supported by the 2021 Milion Do lar Bike Ride Pilot Grant program, provides a wealth of new information to deepen our understanding of the pathologies involved in CADASIL and other smal vessel diseases of the brain and creates a foundation for future therapeutic studies.