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Article ; Online: Analysis of potassium ion diffusion from neurons to capillaries: Effects of astrocyte endfeet geometry.

Djurich, Sara / Secomb, Timothy W

2023 Volume 59, Issue 3, Page(s) 323–332

Abstract: Neurovascular coupling (NVC) refers to a local increase in cerebral blood flow in response to increased neuronal activity. Mechanisms of communication between neurons and blood vessels remain unclear. Astrocyte endfeet almost completely cover cerebral ... ...

Abstract	Neurovascular coupling (NVC) refers to a local increase in cerebral blood flow in response to increased neuronal activity. Mechanisms of communication between neurons and blood vessels remain unclear. Astrocyte endfeet almost completely cover cerebral capillaries, suggesting that astrocytes play a role in NVC by releasing vasoactive substances near capillaries. An alternative hypothesis is that direct diffusion through the extracellular space of potassium ions (K
MeSH term(s)	Astrocytes/physiology ; Capillaries ; Potassium ; Cerebrovascular Circulation ; Neurons
Chemical Substances	Potassium (RWP5GA015D)
Language	English
Publishing date	2023-12-20
Publishing country	France
Document type	Journal Article
ZDB-ID	645180-9
ISSN	1460-9568 ; 0953-816X
ISSN (online)	1460-9568
ISSN	0953-816X
DOI	10.1111/ejn.16232
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Article ; Online: Simulation of Angiogenesis in Three Dimensions: Development of the Retinal Circulation.

Alberding, Jonathan P / Secomb, Timothy W

Bulletin of mathematical biology

2023 Volume 85, Issue 4, Page(s) 27

Abstract: A theoretical model is used to describe the three-dimensional development of the retinal circulation in the human eye, which occurs after the initial spread of vasculature across the inner surface of the retina. In the model, random sprouting ... ...

Abstract	A theoretical model is used to describe the three-dimensional development of the retinal circulation in the human eye, which occurs after the initial spread of vasculature across the inner surface of the retina. In the model, random sprouting angiogenesis is driven by a growth factor that is produced in tissue at a rate dependent on oxygen level and diffuses to existing vessels. Vessel sprouts connect to form pathways for blood flow and undergo remodeling and pruning. These processes are controlled by known or hypothesized vascular responses to hemodynamic and biochemical stimuli, including conducted responses along vessel walls. The model shows regression of arterio-venous connections on the surface of the retina, allowing perfusion of the underlying tissue. A striking feature of the retinal circulation is the formation of two vascular plexuses located at the inner and outer surfaces of the inner nuclear layer within the retina. The model is used to test hypotheses regarding the formation of these structures. A mechanism based on local production and diffusion of growth factor is shown to be ineffective. However, sprout guidance by localized structures on the boundaries of the inner nuclear layer can account for plexus formation. The resulting networks have vascular density, perfusion and oxygen transport characteristics consistent with observed properties. The model shows how stochastic generation of vascular sprouts combined with a set of biologically based response mechanisms can lead to the generation of a specialized three-dimensional vascular structure with a high degree of organization.
MeSH term(s)	Humans ; Retinal Vessels/metabolism ; Models, Biological ; Mathematical Concepts ; Retina ; Oxygen/metabolism
Chemical Substances	Oxygen (S88TT14065)
Language	English
Publishing date	2023-02-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	184905-0
ISSN	1522-9602 ; 0007-4985 ; 0092-8240
ISSN (online)	1522-9602
ISSN	0007-4985 ; 0092-8240
DOI	10.1007/s11538-023-01126-7
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Zs.B 754: Show issues

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Article ; Online: A fast computational model for circulatory dynamics: effects of left ventricle-aorta coupling.

Moulton, Michael J / Secomb, Timothy W

Biomechanics and modeling in mechanobiology

2023 Volume 22, Issue 3, Page(s) 947–959

Abstract: The course of diseases such as hypertension, systolic heart failure and heart failure with a preserved ejection fraction is affected by interactions between the left ventricle (LV) and the vasculature. To study these interactions, a computationally ... ...

Abstract	The course of diseases such as hypertension, systolic heart failure and heart failure with a preserved ejection fraction is affected by interactions between the left ventricle (LV) and the vasculature. To study these interactions, a computationally efficient, biophysically based mathematical model for the circulatory system is presented. In a four-chamber model of the heart, the LV is represented by a previously described low-order, wall volume-preserving model that includes torsion and base-to-apex and circumferential wall shortening and lengthening, and the other chambers are represented using spherical geometries. Active and passive myocardial mechanics of all four chambers are included. The cardiac model is coupled with a wave propagation model for the aorta and a closed lumped-parameter circulation model. Parameters for the normal heart and aorta are determined by fitting to experimental data. Changes in the timing and magnitude of pulse wave reflections by the aorta are demonstrated with changes in compliance and taper of the aorta as seen in aging (decreased compliance, increased diameter and length), and resulting effects on LV pressure-volume loops and LV fiber stress and sarcomere shortening are predicted. Effects of aging of the aorta combined with reduced LV contractile force (failing heart) are examined. In the failing heart, changes in aortic properties with aging affect stroke volume and sarcomere shortening without appreciable augmentation of aortic pressure, and the reflected pressure wave contributes an increased proportion of aortic pressure.
MeSH term(s)	Humans ; Heart Ventricles ; Heart ; Stroke Volume ; Heart Failure ; Aorta ; Ventricular Function, Left
Language	English
Publishing date	2023-01-13
Publishing country	Germany
Document type	Journal Article
ZDB-ID	2093052-5
ISSN	1617-7940 ; 1617-7959
ISSN (online)	1617-7940
ISSN	1617-7959
DOI	10.1007/s10237-023-01690-w
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Zs.A 5966: Show issues

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Article ; Online: Novel method for kinetic analysis applied to transport by the uniporter OCT2.

Wright, Stephen H / Secomb, Timothy W

American journal of physiology. Renal physiology

2022 Volume 323, Issue 3, Page(s) F370–F387

Abstract: The kinetics of solute transport shed light on the roles these processes play in cellular physiology, and the absolute values of the kinetic parameters that quantitatively describe transport are increasingly used to model its impact on drug clearance. ... ...

Abstract	The kinetics of solute transport shed light on the roles these processes play in cellular physiology, and the absolute values of the kinetic parameters that quantitatively describe transport are increasingly used to model its impact on drug clearance. However, accurate assessment of transport kinetics is challenging. Although most carrier-mediated transport is adequately described by the Michaelis-Menten equation, its use presupposes that the rates of uptake used in the analysis of maximal rates of transport (
MeSH term(s)	Animals ; Biological Transport ; CHO Cells ; Cricetinae ; Cricetulus ; Kinetics ; Water
Chemical Substances	Water (059QF0KO0R)
Language	English
Publishing date	2022-07-21
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	603837-2
ISSN	1522-1466 ; 0363-6127
ISSN (online)	1522-1466
ISSN	0363-6127
DOI	10.1152/ajprenal.00106.2022
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Article ; Online: Conditions for Kir-induced bistability of membrane potential in capillary endothelial cells.

Delmoe, Madison / Secomb, Timothy W

Mathematical biosciences

2022 Volume 355, Page(s) 108955

Abstract: A simplified model for electrophysiology of endothelial cells is used to examine the conditions that can lead to bistability of membrane resting potential. The model includes the effects of inward-rectifying potassium (Kir) ion channels, whose current- ... ...

Abstract	A simplified model for electrophysiology of endothelial cells is used to examine the conditions that can lead to bistability of membrane resting potential. The model includes the effects of inward-rectifying potassium (Kir) ion channels, whose current-voltage relationship shows an interval of negative slope and whose maximum conductance is dependent on the extracellular potassium concentration. The background current resulting from other types of channels is assumed to be linearly related to membrane potential. A method is presented for identifying the boundaries in the parameter space for the background currents of the regions of bistability. It is shown that these regions are relatively narrow and depend on extracellular potassium concentration. The results are used to define conditions leading to transitions between depolarized and hyperpolarized membrane states. These behaviors can influence the properties of conducted responses, in which changes in membrane potential are propagated along blood vessel walls. Conducted responses are important in the local regulation of blood flow in the brain and other tissues.
MeSH term(s)	Membrane Potentials/physiology ; Endothelial Cells ; Potassium
Chemical Substances	Potassium (RWP5GA015D)
Language	English
Publishing date	2022-12-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1126-5
ISSN	1879-3134 ; 0025-5564
ISSN (online)	1879-3134
ISSN	0025-5564
DOI	10.1016/j.mbs.2022.108955
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Zs.A 1534: Show issues

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Article ; Online: Spreading mechanics and differentiation of astrocytes during retinal development.

Stepien, Tracy L / Secomb, Timothy W

Journal of theoretical biology

2022 Volume 549, Page(s) 111208

Abstract: The retinal vasculature supplies oxygen to the inner layers of the retina, the light-sensitive tissue in the eye. During development, formation of the retinal vasculature depends on prior establishment of a mesh of astrocytes, a type of glial cell, which ...

Abstract	The retinal vasculature supplies oxygen to the inner layers of the retina, the light-sensitive tissue in the eye. During development, formation of the retinal vasculature depends on prior establishment of a mesh of astrocytes, a type of glial cell, which guide the growth of the vascular network. Astrocytes emerge from the optic nerve head and proliferate and spread, forming a mesh-like layer over the retinal surface. The initially formed cells are termed astrocyte precursor cells (APCs), which differentiate into immature perinatal astrocytes (IPAs) during the prenatal period. A continuum model is developed to describe the proliferation, differentiation, and migration these cells. Effects of oxygen and growth factor levels on proliferation and differentiation are included. Cell migration is driven by gradients in tension in the astrocyte mesh, which varies inversely with total density. The resulting governing equations have the form of a nonlinear diffusion-like equation. The model can account for the observed radial spread over time of the astrocyte disk. Experimental observations show that the APCs form a narrow rim around the edge of this disk, with IPAs in the interior. The model predicts this behavior if the mobility of the APCs is assumed to be higher than that of the IPAs under a given tension gradient. Thus, the model shows how tension-driven cell motions can account for separation of cell types in a cell layer spreading over a substrate.
MeSH term(s)	Astrocytes/metabolism ; Cell Differentiation ; Cell Movement/physiology ; Female ; Humans ; Oxygen/metabolism ; Pregnancy ; Retina/metabolism
Chemical Substances	Oxygen (S88TT14065)
Language	English
Publishing date	2022-07-04
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2972-5
ISSN	1095-8541 ; 0022-5193
ISSN (online)	1095-8541
ISSN	0022-5193
DOI	10.1016/j.jtbi.2022.111208
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Article ; Online: Functional implications of microvascular heterogeneity for oxygen uptake and utilization.

Roy, Tuhin K / Secomb, Timothy W

Physiological reports

2022 Volume 10, Issue 10, Page(s) e15303

Abstract: In the vascular system, an extensive network structure provides convective and diffusive transport of oxygen to tissue. In the microcirculation, parameters describing network structure, blood flow, and oxygen transport are highly heterogeneous. This ... ...

Abstract	In the vascular system, an extensive network structure provides convective and diffusive transport of oxygen to tissue. In the microcirculation, parameters describing network structure, blood flow, and oxygen transport are highly heterogeneous. This heterogeneity can strongly affect oxygen supply and organ function, including reduced oxygen uptake in the lung and decreased oxygen delivery to tissue. The causes of heterogeneity can be classified as extrinsic or intrinsic. Extrinsic heterogeneity refers to variations in oxygen demand in the systemic circulation or oxygen supply in the lungs. Intrinsic heterogeneity refers to structural heterogeneity due to stochastic growth of blood vessels and variability in flow pathways due to geometric constraints, and resulting variations in blood flow and hematocrit. Mechanisms have evolved to compensate for heterogeneity and thereby improve oxygen uptake in the lung and delivery to tissue. These mechanisms, which involve long-term structural adaptation and short-term flow regulation, depend on upstream responses conducted along vessel walls, and work to redistribute flow and maintain blood and tissue oxygenation. Mathematically, the variance of a functional quantity such as oxygen delivery that depends on two or more heterogeneous variables can be reduced if one of the underlying variables is controlled by an appropriate compensatory mechanism. Ineffective regulatory mechanisms can result in poor oxygen delivery even in the presence of adequate overall tissue perfusion. Restoration of endothelial function, and specifically conducted responses, should be considered when addressing tissue hypoxemia and organ failure in clinical settings.
MeSH term(s)	Adaptation, Physiological ; Hemodynamics ; Humans ; Hypoxia ; Microcirculation/physiology ; Oxygen/metabolism ; Oxygen Consumption
Chemical Substances	Oxygen (S88TT14065)
Language	English
Publishing date	2022-03-09
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural
ZDB-ID	2724325-4
ISSN	2051-817X ; 2051-817X
ISSN (online)	2051-817X
ISSN	2051-817X
DOI	10.14814/phy2.15303
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Article ; Online: Simulation of angiogenesis in three dimensions: Application to cerebral cortex.

Alberding, Jonathan P / Secomb, Timothy W

PLoS computational biology

2021 Volume 17, Issue 6, Page(s) e1009164

Abstract: The vasculature is a dynamic structure, growing and regressing in response to embryonic development, growth, changing physiological demands, wound healing, tumor growth and other stimuli. At the microvascular level, network geometry is not predetermined, ...

Abstract	The vasculature is a dynamic structure, growing and regressing in response to embryonic development, growth, changing physiological demands, wound healing, tumor growth and other stimuli. At the microvascular level, network geometry is not predetermined, but emerges as a result of biological responses of each vessel to the stimuli that it receives. These responses may be summarized as angiogenesis, remodeling and pruning. Previous theoretical simulations have shown how two-dimensional vascular patterns generated by these processes in the mesentery are consistent with experimental observations. During early development of the brain, a mesh-like network of vessels is formed on the surface of the cerebral cortex. This network then forms branches into the cortex, forming a three-dimensional network throughout its thickness. Here, a theoretical model is presented for this process, based on known or hypothesized vascular response mechanisms together with experimentally obtained information on the structure and hemodynamics of the mouse cerebral cortex. According to this model, essential components of the system include sensing of oxygen levels in the midrange of partial pressures and conducted responses in vessel walls that propagate information about metabolic needs of the tissue to upstream segments of the network. The model provides insights into the effects of deficits in vascular response mechanisms, and can be used to generate physiologically realistic microvascular network structures.
MeSH term(s)	Animals ; Cerebral Cortex/blood supply ; Cerebral Cortex/growth & development ; Computational Biology ; Computer Simulation ; Hemodynamics/physiology ; Mice ; Microcirculation/physiology ; Microvessels/anatomy & histology ; Microvessels/growth & development ; Microvessels/physiology ; Models, Cardiovascular ; Models, Neurological ; Neovascularization, Physiologic ; Oxygen Consumption
Language	English
Publishing date	2021-06-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2193340-6
ISSN	1553-7358 ; 1553-734X
ISSN (online)	1553-7358
ISSN	1553-734X
DOI	10.1371/journal.pcbi.1009164
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Article ; Online: Distinct roles of red-blood-cell-derived and wall-derived mechanisms in metabolic regulation of blood flow.

Fry, Brendan C / Secomb, Timothy W

Microcirculation (New York, N.Y. : 1994)

2021 Volume 28, Issue 5, Page(s) e12690

Abstract: Objective: A theoretical model is used to analyze combinations of RBC-derived and wall-derived (RBC-independent) mechanisms for metabolic blood flow regulation, with regard to their oxygen transport properties.: Methods: Heterogeneous microvascular ... ...

Abstract	Objective: A theoretical model is used to analyze combinations of RBC-derived and wall-derived (RBC-independent) mechanisms for metabolic blood flow regulation, with regard to their oxygen transport properties. Methods: Heterogeneous microvascular network structures are derived from observations in rat mesentery and hamster cremaster. The effectiveness of metabolic blood flow regulation using combinations of RBC-dependent and RBC-independent mechanisms is simulated in these networks under conditions of reduced oxygen delivery and increased oxygen demand. Results: Metabolic regulation by a wall-derived mechanism results in higher predicted total blood flow rate and number of flowing vessels, and lower tissue hypoxic fraction, than regulation by combinations of RBC-derived and wall-derived signals. However, a combination of RBC-derived and wall-derived signals results in a higher predicted median tissue P Conclusions: Model results suggest complementary roles for RBC-derived and wall-derived mechanisms of metabolic flow regulation, with the wall-derived mechanism responsible for avoiding hypoxia, and the RBC-derived mechanism responsible for maintaining P
MeSH term(s)	Animals ; Cricetinae ; Erythrocytes ; Hematocrit ; Hemodynamics ; Hypoxia ; Oxygen ; Oxygen Consumption ; Rats
Chemical Substances	Oxygen (S88TT14065)
Language	English
Publishing date	2021-03-18
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1217758-1
ISSN	1549-8719 ; 1073-9688
ISSN (online)	1549-8719
ISSN	1073-9688
DOI	10.1111/micc.12690
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Article ; Online: An autonomous mathematical model for the mammalian cell cycle.

Williams, Katherine S / Secomb, Timothy W / El-Kareh, Ardith W

Journal of theoretical biology

2023 Volume 569, Page(s) 111533

Abstract: A mathematical model for the mammalian cell cycle is developed as a system of 13 coupled nonlinear ordinary differential equations. The variables and interactions included in the model are based on detailed consideration of available experimental data. A ...

Abstract	A mathematical model for the mammalian cell cycle is developed as a system of 13 coupled nonlinear ordinary differential equations. The variables and interactions included in the model are based on detailed consideration of available experimental data. A novel feature of the model is inclusion of cycle tasks such as origin licensing and initiation, nuclear envelope breakdown and kinetochore attachment, and their interactions with controllers (molecular complexes involved in cycle control). Other key features are that the model is autonomous, except for a dependence on external growth factors; the variables are continuous in time, without instantaneous resets at phase boundaries; mechanisms to prevent rereplication are included; and cycle progression is independent of cell size. Eight variables represent cell cycle controllers: the Cyclin D1-Cdk4/6 complex, APC
MeSH term(s)	Animals ; Separase ; Cell Cycle/physiology ; Cell Cycle Proteins/metabolism ; Cell Division ; Mammals ; Models, Theoretical
Chemical Substances	Separase (EC 3.4.22.49) ; Cell Cycle Proteins
Language	English
Publishing date	2023-05-15
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2972-5
ISSN	1095-8541 ; 0022-5193
ISSN (online)	1095-8541
ISSN	0022-5193
DOI	10.1016/j.jtbi.2023.111533
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