Theoretical Investigations of Communication in the Microcirculation: Conducted Responses, Myoendothelial Projections and Endothelium Derived Hyperpolarizing Factor

Authors

Sridevi Nagaraja, Florida International UniversityFollow

Document Type

Dissertation

Degree

Doctor of Philosophy (PhD)

Major/Program

Biomedical Engineering

First Advisor's Name

Nikolaos Tsoukias

First Advisor's Committee Title

Committee Chair

Second Advisor's Name

Wei-Chiang Lin

Third Advisor's Name

Anuradha Godavarty

Fourth Advisor's Name

Lidia Kos

Fifth Advisor's Name

Yen-Chih Huang

Keywords

intercellular communication, calcium dynamics, myoendothelial feedback, gap junction coupling, potassium accumulation

Date of Defense

11-7-2011

Abstract

The contractile state of microcirculatory vessels is a major determinant of the blood pressure of the whole systemic circulation. Continuous bi-directional communication exists between the endothelial cells (ECs) and smooth muscle cells (SMCs) that regulates calcium (Ca²⁺) dynamics in these cells. This study presents theoretical approaches to understand some of the important and currently unresolved microcirculatory phenomena.

Agonist induced events at local sites have been shown to spread long distances in the microcirculation. We have developed a multicellular computational model by integrating detailed single EC and SMC models with gap junction and nitric oxide (NO) coupling to understand the mechanisms behind this effect. Simulations suggest that spreading vasodilation mainly occurs through Ca²⁺ independent passive conduction of hyperpolarization in RMAs. Model predicts a superior role for intercellular diffusion of inositol (1,4,5)-trisphosphate (IP₃) than Ca²⁺ in modulating the spreading response.

Endothelial derived signals are initiated even during vasoconstriction of stimulated SMCs by the movement of Ca²⁺ and/or IP₃ into the EC which provide hyperpolarizing feedback to SMCs to counter the ongoing constriction. Myoendothelial projections (MPs) present in the ECs have been recently proposed to play a role in myoendothelial feedback. We have developed two models using compartmental and 2D finite element methods to examine the role of these MPs by adding a sub compartment in the EC to simulate MP with localization of intermediate conductance calcium activated potassium channels (IK_Ca) and IP₃ receptors (IP₃R). Both models predicted IP₃ mediated high Ca²⁺ gradients in the MP after SMC stimulation with limited global spread. This Ca²⁺ transient generated a hyperpolarizing feedback of ~ 2-3mV.

Endothelium derived hyperpolarizing factor (EDHF) is the dominant form of endothelial control of SMC constriction in the microcirculation. A number of factors have been proposed for the role of EDHF but no single pathway is agreed upon. We have examined the potential of myoendothelial gap junctions (MEGJs) and potassium (K⁺) accumulation as EDHF using two models (compartmental and 2D finite element). An extra compartment is added in SMC to simulate micro domains (MD) which have NaK_α2 isoform sodium potassium pumps. Simulations predict that MEGJ coupling is much stronger in producing EDHF than alone K⁺ accumulation. On the contrary, K⁺ accumulation can alter other important parameters (EC V_m, IK_Ca current) and inhibit its own release as well as EDHF conduction via MEGJs. The models developed in this study are essential building blocks for future models and provide important insights to the current understanding of myoendothelial feedback and EDHF.

Identifier

FI11120802

Recommended Citation

Nagaraja, Sridevi, "Theoretical Investigations of Communication in the Microcirculation: Conducted Responses, Myoendothelial Projections and Endothelium Derived Hyperpolarizing Factor" (2011). FIU Electronic Theses and Dissertations. 520.
https://digitalcommons.fiu.edu/etd/520