The overall goal of Dr. Wellman’s research is to understand how cerebral artery diameter is regulated during health and disease. A major emphasis in the lab is to understand and target cell signaling pathways contributing to enhanced cerebral artery constriction following cerebral aneurysm rupture and subarachnoid hemorrhage (SAH). Aneurysmal SAH occurs in approximately 30,000 people each year in the United States and is associated with high rates of morbidity and mortality. Current treatment strategies for this type of stroke are limited and do little to improve patient outcome.
We have identified a dual-system molecular module centered on activation of the epidermal growth factor receptor (EGFR) in both arteriolar smooth muscle and the astrocyte endfeet that encase these arterioles within the brain parenchyma. Our discovery that EGFR activation is the linchpin of two distinct pathways - one in smooth muscle and one in astrocytes - converging to decrease CBF after SAH represents a significant breakthrough that could lay the groundwork for developing new therapeutic interventions targeting EGFRs in SAH patients. Importantly, EGFR antagonists are currently approved by the FDA as anticancer agents and are generally well tolerated. Our ongoing studies include the use of newly developed strains of transgenic mice and state-of-the-art in vivo imaging of arterial smooth muscle and astrocyte Ca2+ signaling, arteriolar diameter and CBF.
We have also recently made the first optical measurements of elementary Ca2+ signals generated by smooth muscle TRPV1 channels. TRPV1 channels are "non-selective" Ca2+-permeable channels characterized by there polymodal activation by noxious stimuli (e.G., heat, acidic pH, capsaicin). These channels, which are widely expressed in sensory nerves, have largely been examined through the lens of pain. Our new findings reveal striking patterns of TRPV1 expression in different vascular beds, showing for example that TRPV1 are expressed in arterial smooth muscle of the external carotid artery territory, but not in cerebral arteries or the internal carotid arteries that feed them.
Our data supports the concept that activation of TRPV1 tunes vascular resistance in the external carotid artery territory, serving as a mechanism for redistributing blood flow to internal carotid arteries and the brain. Our use of genetically-encoded Ca2+ indicator mice, TRPV1-defficient mice and our recently developed TRPV1-tdTomato reporter mice provide an unparalleled approach to study vascular TRPV1 function from the single molecule to the intact animal.
Dr. Wellman’s research combines a variety of experimental techniques to study how blood released onto the brain surface causes changes in electrical activity and calcium signaling leading to smooth muscle contraction. Our studies have revealed that subarachnoid blood can have profound effects on plasma membrane Ca2+ and K+ channel activity, as well as the frequency of intracellular Ca2+ release events (Ca2+ sparks). We have also demonstrated fundamental changes in local and global calcium signaling within the neurovascular unit (neurons, astrocytes and parenchymal arterioles) of subarachnoid hemorrhage model animals. Specifically, in the context of brain slices where communication between neurons, astrocytes and the vasculature is intact (i.e., the intact neurovascular unit), we have novel and exciting evidence that subarachnoid hemorrhage causes a shift in neurovascular coupling from vasodilation to vasoconstriction.
Techniques in the lab include:
- patch clamp electrophysiology to measure ion channel activity
- laser scanning confocal microscopy, multi-photon microscopy and conventional epifluorescence microscopy to examine local and global intracellular calcium concentrations in arterial myocytes and astrocytic endfeet
- molecular biology and biochemical approaches including qualitative real- time PCR and western blot
- in vitro functional measurements of cerebral artery diameter.
Joseph E. Brayden, Ph.D., Emeritus Professor
Masayo Koide, Ph.D. Research Assistant Professor
Hannah Ferris, M.S., Technician
Grace Vorhees, M.S., Technician