Insights into cerebral haemodynamics and oxygenation utilising in vivo mural cell imaging and mathematical modelling

Abstract

The neurovascular mechanisms underpinning the local regulation of cerebral blood flow (CBF) and oxygen transport remain elusive. In this study we have combined novel in vivo imaging of cortical microvascular and mural cell architecture with mathematical modelling of blood flow and oxygen transport, to provide new insights into CBF regulation that would be inaccessible in a conventional experimental context. Our study indicates that vasoconstriction of smooth muscle actin-covered vessels, rather than pericyte-covered capillaries, induces stable reductions in downstream intravascular capillary and tissue oxygenation. We also propose that seemingly paradoxical observations in the literature around reduced blood velocity in response to arteriolar constrictions might be caused by a propagation of constrictions to upstream penetrating arterioles. We provide support for pericytes acting as signalling conduits for upstream smooth muscle activation, and erythrocyte deformation as a complementary regulatory mechanism. Finally, we caution against the use of blood velocity as a proxy measurement for flow. Our combined imaging-modelling platform complements conventional experimentation allowing cerebrovascular physiology to be probed in unprecedented detail.

Computational fluid dynamics with imaging of cleared tissue and of in vivo perfusion predicts drug uptake and treatment responses in tumours

“…Blood flow through the segmented vascular network was modelled by Poiseuille's law, using empirically-derived laws for blood viscosity (assuming constant network haematocrit) and following the established approach developed in 70,71 and applied to numerous tissues (for example mesentery, 72,73 muscle, cortex, 75 and tumours 54,76 ). This model assumes conservation of flux at vessel junctions to define a linear system to solve for the pressures at nodal points in the network (from which vessel fluxes are calculated using Poiseuille).…”

Modelling the transport of fluid through heterogeneous, whole tumours in silico

“…The scheme estimates sensitivity is weighted towards the definition of these two target parameters. This 150 enables physiologically realistic blood pressure and flow distributions to be estimated 151 across an entire vascular network and has been applied to breast tumour [44], colorectal 152 December 24, 2018 7/36 tumours [38], cortex [45], glioma [38] and skeletal muscle [46]. 153 The second component to our computational model describes fluid transport 154 through the porous interstitium using a Darcy model, coupled to the vascular flow 155 solution via Starling's law which describes fluid transport across the endothelium.…”

“…The 156 vasculature is represented by a discrete set of points sources of flux where the source 157 strengths are defined by the vascular blood flow solution. A similar approach has been 158 applied to simulate O 2 transport across various tissues [40,45,47]. Our approach 159 enables us to explore the effect of vascular architecture heterogeneity on fluid transport 160 within the interstitium for large-scale vascular networks.…”

“…The blood flow estimation model by Fry et al [39] has been thoroughly tested using 202 mesenteric networks [50] in which blood flow measurements were taken in individual 203 vessels and used to inform parameter estimation [39,42,48,51]. Darcy's law has been effectively used to describe the passage of fluids [3,14,[30][31][32][33]52] or 206 solutes [40,45] through tissues. In this study, we use Darcy's law to describe the 207 relationship between the volume-averaged IFP, p, and interstitial fluid velocity (IFV), u, 208 within the porous interstitial domain:…”

The pericyte microenvironment during vascular development

“…Intriguing nuances within these more “canonical” roles are still being discovered in health and in diseases such as proliferative diabetic retinopathy, cancer and metastatic progression, and Alzheimer's disease . Pericyte contractility, or the modulation of microvessel diameter, is an area of ongoing investigation, particularly in the central nervous system (CNS) . In addition, the tissue regeneration capacity of pericytes, acting as a pool of perivascular mesenchymal stem cells, has also been described as a potential role for these cells .…”