Brain Capillary Mechanosensation by Piezo1 Channels in Health and Disease

As blood moves through a narrow brain blood vessel, it imposes mechanical forces on the vessel wall, raising an important question: do capillaries (the very smallest blood vessels) sense the forces associated with flowing blood? This research will examine how blood vessels sense these forces and influence changes in blood flow in the mouse brain using genetically engineered mice and advanced imaging techniques. The ultimate goal of these studies is to provide results that lead to strategies for preventing deficits in brain blood flow in human diseases such as hypertension, which plays a major role in brain aging.

Crippled Cerebral Blood Flow Regulation in Chronic Hypertension 

Research Summary: Cerebral blood flow is exquisitely controlled to meet the diverse and ever-changing demands of active neurons throughout the brain. This moment-to-moment adjustment of local blood flow, observed as increased cerebral blood flow within active regions of brain, is known as functional hyperemia. Dr. Koide’s recent work has demonstrated a novel signaling pathway, capillary-to-arteriole electrical signaling, which is a major contributor to functional hyperemia. Her proposed research will examine 1) the impact of chronic hypertension on functional hyperemia, specifically on capillary-to-arteriole electrical signaling, and 2) the molecular mechanism of impaired functional hyperemia, centering on plasma aldosterone as a crucial player, in a murine model of polygenic hypertension. Hypertension is the leading risk factor for cardiovascular and cerebrovascular diseases and affects an estimated 80 million people in the United States and 1 billion individuals worldwide. Although a growing body of evidence indicates that hypertension attenuates functional hyperemia, and contributes to impaired cognitive function in humans as well as in hypertensive animals, the mechanisms underlying this pathophysiological process have yet to be elucidated.

Project Director:

Masayo Koide, Ph.D.

Research Assistant Professor
Department of Pharmacology

Extracellular Drivers of Myocyte Stiffening in Diastolic Heart Disease 

Diastolic heart disease arises from combined hypertension and metabolic syndrome, and it is the leading cause of death and disability worldwide.  Diastole depends on a heart’s stiffness and ability to relax or to reduce active tension. Diastolic dysfunction is the hallmark of diastolic heart disease. However, its molecular underpinnings are controversial and are thought to involve sarcomeres (the contractile unit of muscle), the microtubule network (a cellular mesh of stiff cytoskeletal filaments) and extracellular fibrosis. The role of the microtubule network in diastolic heart disease remains largely unexplored; however, data from heart failure studies show that the microtubule network regulates the stiffness and relaxation of cardiomyocytes. We hypothesize that the microtubule network contributes to cardiomyocyte-level stiffening and diastolic dysfunction in diastolic heart failure.  To test this, we will use rat models of hypertension and diastolic heart disease to evaluate microtubule network-based stiffening. We will combine our unique expertise in microtubule network structural dynamics, proteomics and mechanics with a novel working myocardial preparation to evaluate the contribution of sarcomeres, fibrosis and the microtubule network on myocardial diastolic performance (Fig 1). We anticipate that only rats with diastolic heart failure will exhibit impaired relaxation. Our ultimate goal is to determine the molecular basis of diastolic dysfunction and the potential of microtubule network-based therapies for hypertension and diastolic heart disease.