Modeling Ca2+ signaling in the microcirculation: intercellular communication and vasoreactivity

Abstract

A network of intracellular signaling pathways and complex intercellular interactions regulate calcium mobilization in vascular cells, arteriolar tone, and blood flow. Different endothelium-derived vasoreactive factors have been identified and the importance of myoendothelial communication in vasoreactivity is now well appreciated. The ability of many vascular networks to conduct signals upstream also is established. This phenomenon is critical for both short-term changes in blood perfusion as well as long-term adaptations of a vascular network. In addition, in a phenomenon termed vasomotion, arterioles often exhibit spontaneous oscillations in diameter. This is thought to improve tissue oxygenation and enhance blood flow. Experimentation has begun to reveal important aspects of the regulatory machinery and the significance of these phenomena for the regulation of local perfusion and oxygenation. Mathematical modeling can assist in elucidating the complex signaling mechanisms that participate in these phenomena. This review highlights some of the important experimental studies and relevant mathematical models that provide the current understanding of these mechanisms in vasoreactivity.

FIGURE 1

Experimental characterization of microprojections (MP) and their functional role in myoendothelial feedback. (A) Electron microscopy images of an endothelial microprojection in rat saphenous arteries. Reproduced with permission from Sandow et al.. Copyright 2004, John Wiley & Sons, Inc. (B, C) Immunohistochemical labeling studies in rat mesenteric artery showing localization of IK_Ca channels and IP₃R receptors on the projections. Reproduced with permission from Ledoux et al.90. Copyright 2008, National Academy of Sciences. (D) Proposed mechanism of myoendothelial feedback involves IP₃ diffusion from smooth muscle cell (SMC) to endothelial cell (EC) MP (1), activation of IP₃R and increase of Ca²⁺ in MP (2), activation of IK_Ca channels (3), and hyperpolarizing current in EC (4) and SMC (5).

FIGURE 2

(A) Schematic diagram of compartmental endothelial cell (EC)-smooth muscle cell (SMC) model with endothelial MPs showing membrane and cytosolic components and their localization as implemented by Kapela et al. (B) Two-dimensional mesh of the finite element method model with endothelial MPs and extracellular cleft. (C) Predicted Ca²⁺ transients in the MP during norepinephrine stimulation of SMC.

FIGURE 3

Computational model of spreading responses. (A) Assumed arrangement of discrete endothelial cells (ECs) and smooth muscle cells (SMCs) into an isolated vessel segment. (B) Predicted EC Ca²⁺ elevation induced by focal acetylcholine (Ach) stimulation at x=0 had limited spread from the local site. (C) Local Ach-induced EC hyperpolarization was conducted to distant ECs through endothelial gap junctions. (D) SMC Ca²⁺ was reduced at local and distant sites by hyperpolarizing current transmitted from ECs through myoendothelial gap juctions. Reproduced with permission from Kapela et al. Copyright 2010, The American Physiological Society.

FIGURE 4

Schematic diagram of possible Ca²⁺ synchronization pathways in vascular smooth muscle cells (SMCs). Ca²⁺ increase in first cell (left) can activate directly Cl_Ca and BK_Ca channels, and indirectly nonselective cation (NSC)channels through Ca²⁺-sensitive phospholipase C (PLC) and diacylglycerol (DAG). The activation of NSC and/or Cl_Ca depolarizes V_m (solid green lines), although their effect may be moderated by BK_Ca channels (solid red line). The depolarization spreads through gap junctions to neighboring cells (right), activates voltage-operated Ca²⁺ channels and increases in-phase cytosolic Ca²⁺. Ca²⁺ elevation in one cell can increase Ca²⁺ in neighboring cells by direct diffusion of Ca²⁺ through the gap junctions. Oscillatory IP₃, generated by Ca²⁺-dependent PLC and diffusing to other cells, may also have synchronizing effect by acting on IP₃ receptors.