Electromechanical Dynamics and Myogenic Responses in Cerebral Smooth Muscle Cells and Capillary Pericytes

Cerebral blood flow (CBF) control is essential for normal brain function and is disrupted in pathological conditions. Arterial diameters are tightly regulated to provide on demand increases in blood flow in regions of neuronal activity. Pericytes (PCs) exhibit robust myogenic tone and may also respond to neuronal activity to fine-tune local resistance and blood flow. Thus, mural control of microcirculatory resistance may extend beyond arteries and arterioles. Yet, PC's electrophysiology and contractility have not been thoroughly characterized, and this prohibits an integrated view of brain blood flow control. In this study, we develop a detailed mathematical model of mural cell electrophysiology, Ca ²⁺ dynamics and biomechanics. The model is informed by electrophysiological data in smooth muscle cells (SMCs) or PCs and predictions are compared against pressure-induced responses in isolated arterioles and capillaries, respectively. Simulations recapitulate myogenic constrictions and examine differences in contractile dynamics as we move from arterioles to proximal and distal capillaries. In arteriole-to-capillary transitional (ACT) zone PCs, increased mechanosensitivity, more Ca ²⁺ influx through non-selective cation (NSC) channels and/or a higher sensitivity of the contractile apparatus to Ca ²⁺ can compensate for reduced L-type voltage-operated (VOCC) Ca ²⁺ influx and allow for robust constrictions at the lower operating pressures of capillaries relative to the arterioles. A significant Ca ²⁺ influx through NSC relative to VOCC, however, can decouple the PC's contractile apparatus from electrical signaling. Vasoactivity to chemomechanical stimuli along the arteriole to capillary axis is progressively driven by VOCC-independent Ca ²⁺ influx and Ca ²⁺ sensitization with slow kinetics. The proposed cell model can form the basis for detailed multiscale and multicellular models that will examine physiological function at a single vessel or vascular network levels and investigate CBF control in health and in disease.

A mural cell model of electrophysiology, calcium (Ca ²⁺ ) dynamics and biomechanics is informed by data and adapted for modeling cerebral arteriole smooth muscle cells and capillary pericytes. Ion channel activities are characterized by patch-clamp electrophysiology in isolated cerebral smooth muscle cell and pericytes, and capillary and arteriole electromechanical responses to transmural pressure changes are assessed using novel ex vivo preparations. Myogenic constrictions in arterioles can be reproduced by pressure-induced non-selective cation channel (NSC) activation that depolarizes the cell, opens L-type Ca ²⁺ channels (VOCCs) and increases Ca ²⁺ influx. Robust myogenic constrictions in arteriole-to-capillary transition (ACT) zone pericytes may reflect significant Ca ²⁺ influx through NSC, increased mechanosensitivity, or higher sensitivity of the contractile apparatus to Ca ²⁺ , potentially compensating for reduced VOCC density relative to arteriolar smooth muscle. A significant contribution of NSC relative to VOCC in Ca ²⁺ influx, can decouple the contractile apparatus from electrical signaling. The model shows how gradients in ionic activities, mechanosensitivity and/or Ca ²⁺ sensitivity can alter contractile phenotype and electromechanical coupling along the arteriole to capillary continuum. The proposed model can form the basis for detailed multiscale and multicellular models that will investigate cerebral blood flow control in health and in disease.