The Microvascular System of the Striate and Extrastriate Visual Cortex of the Macaque

In functional neuroimaging, neurovascular coupling is used to generate maps of hemodynamic changes that are assumed to be surrogates of regional neural activation. The aim of this study was to characterize the microvascular system of the primate cortex as a basis for understanding the constraints imposed on a region's hemodynamic response by the vascular architecture, density, as well as area- and layer-specific variations. In the macaque visual cortex, an array of anatomical techniques has been applied, including corrosion casts, immunohistochemistry, and cytochrome oxidase (COX) staining. Detailed measurements of regional vascular length density, volume fraction, and surface density revealed a similar vascularization in different visual areas. Whereas the lower cortical layers showed a positive correlation between the vascular and cell density, this relationship was very weak in the upper layers. Synapse density values taken from the literature also displayed a very moderate correlation with the vascular density. However, the vascular density was strongly correlated with the steady-state metabolic demand as measured by COX activity. This observation suggests that although the number of neurons and synapses determines an upper bound on an area's integrative capacity, its vascularization reflects the neural activity of those subpopulations that represent a "default” mode of brain steady stat

Genetic Deletion of Laminin Isoforms β2 and γ3 Induces a Reduction in Kir4.1 and Aquaporin-4 Expression and Function in the Retina

Glial cells such as retinal Müller glial cells are involved in potassium ion and water homeostasis of the neural tissue. In these cells, inwardly rectifying potassium (Kir) channels and aquaporin-4 water channels play an important role in the process of spatial potassium buffering and water drainage. Moreover, Kir4.1 channels are involved in the maintenance of the negative Müller cell membrane potential. The subcellular distribution of Kir4.1 and aquaporin-4 channels appears to be maintained by interactions with extracellular and intracellular molecules. Laminins in the extracellular matrix, dystroglycan in the membrane, and dystrophins in the cytomatrix form a complex mediating the polarized expression of Kir4.1 and aquaporin-4 in Müller cells.The aim of the present study was to test the function of the β2 and γ3 containing laminins in murine Müller cells. We used knockout mice with genetic deletion of both β2 and γ3 laminin genes to assay the effects on Kir4.1 and aquaporin-4. We studied protein and mRNA expression by immunohistochemistry, Western Blot, and quantitative RT-PCR, respectively, and membrane currents of isolated cells by patch-clamp experiments. We found a down-regulation of mRNA and protein of Kir4.1 as well as of aquaporin-4 protein in laminin knockout mice. Moreover, Müller cells from laminin β2 and γ3 knockout mice had reduced Kir-mediated inward currents and their membrane potentials were more positive than those in age-matched wild-type mice.These findings demonstrate a strong impact of laminin β2 and γ3 subunits on the expression and function of both aquaporin-4 and Kir4.1, two important membrane proteins in Müller cells

The impact of capillary dilation on the distribution of red blood cells in artificial networks

Recent studies suggest that pericytes around capillaries are contractile and able to alter the diameter of capillaries. To investigate the effects of capillary dilation on network dynamics, we performed simulations in artificial capillary networks of different sizes and complexities. The unequal partition of hematocrit at diverging bifurcations was modeled by assuming that each red blood cell (RBC) enters the branch with the faster instantaneous flow. Network simulations with and without RBCs were performed to investigate the effect of local dilations. The results showed that the increase in flow rate due to capillary dilation was less when the effects of RBCs are included. For bifurcations with sufficient RBCs in the parent vessel and nearly equal flows in the branches, the flow rate in the dilated branch did not increase. Instead, a self-regulation of flow was observed due to accumulation of RBCs in the dilated capillary. A parametric study was performed to examine the dependence on initial capillary diameter, dilation factor, and tube hematocrit. Furthermore, the conditions needed for an efficient self-regulation mechanism are discussed. The results support the hypothesis that RBCs play a significant role for the fluid dynamics in capillary networks and that it is crucial to consider the blood flow rate and the distribution of RBCs to understand the supply of oxygen in the vasculature. Furthermore, our results suggest that capillary dilation/constriction offers the potential of being an efficient mechanism to alter the distribution of RBCs locally and hence could be important for the local regulation of oxygen delivery

A Coupled Discrete/Continuum Model for Describing Cancer-Therapeutic Transport in the Lung

We propose a computational simulation framework for describing cancer-therapeutic transport in the lung. A discrete vascular graph model (VGM) is coupled to a double-continuum model (DCM) to determine the amount of administered therapeutic agent that will reach the cancer cells. An alveolar cell carcinoma is considered. The processes in the bigger blood vessels (arteries, arterioles, venules and veins) are described by the VGM. The processes in the alveolar capillaries and the surrounding tissue are represented by a continuum approach for porous media. The system of equations of the coupled discrete/continuum model contains terms that account for degradation processes of the therapeutic agent, the reduction of the number of drug molecules by the lymphatic system and the interaction of the drug with the tissue cells. The functionality of the coupled discrete/continuum model is demonstrated in example simulations using simplified pulmonar

Vascular graph model to simulate the cerebral blood flow in realistic vascular networks

At its most fundamental level, cerebral blood flow (CBF) may be modeled as fluid flow driven through a network of resistors by pressure gradients. The composition of the blood as well as the cross-sectional area and length of a vessel are the major determinants of its resistance to flow. Here, we introduce a vascular graph modeling framework based on these principles that can compute blood pressure, flow and scalar transport in realistic vascular networks. By embedding the network in a computational grid representative of brain tissue, the interaction between the two compartments can be captured in a truly three-dimensional manner and may be applied, among others, to simulate oxygen extraction from the vessels. Moreover, we have devised an upscaling algorithm that significantly reduces the computational expense and eliminates the need for detailed knowledge on the topology of the capillary bed. The vascular graph framework has been applied to investigate the effect of local vascular dilation and occlusion on the flow in the surrounding network

Tissue metabolism driven arterial tree generation

We present an approach to generate 3-D arterial tree models based on physiological principles while at the same time certain morphological properties are enforced at construction time. The driving force of the construction is a simplified angiogenesis model incorporating case-specific information about the metabolic demand within the considered domain. The vascular tree is constructed iteratively by successively adding new segments in chemotactic response to angiogenic growth factors secreted by ischemic cells. Morphometrically confirmed bifurcation statistics of vascular networks are incorporated to optimize the synthetic vasculature. The proposed method is able to generate artificial, yet physiologically plausible, arterial tree models that match the metabolic demand of the embedding tissue and fulfill the prescribed morphological properties at the same time. The proposed tree generation approach is applied in a simulation setup based on the metabolic configuration and anatomy of the macaque visual cortex. We analyze the generated tree models with respect to morphological and physiological aspects including fluid-dynamic simulations. The comparison of our results with the findings of different studies on the structure of cerebral vasculatures demonstrates the plausibility of our method

Computation of the effective permeability of a REV.

<p>Fixed pressures and set at all nodes crossing the left and right face normal to x respectively (no-flow boundary condition at all nodes crossing the other four faces). Effective permeability computed from pressure gradient and integral mass flow through the REV's capillary network (image modified from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0031966#pone.0031966-Reichold1" target="_blank">[9]</a>).</p

Visualization of the vascular graph coupled to the DCM.

<p>The black lines represent the blood vessels, which form the unstructured grid of the VGM. The red nodes and the blue rectangles symbolize the capillary bed and pulmonary tissue around an alveolus, which are simulated using the DCM. The red nodes are the healthy upscaled nodes and the blue rectangles are the tumorous ones. The blood vessels above/below the alveoli are arteries/veins of the order one to four, with a morphology according to <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0031966#pone-0031966-t001" target="_blank">Table 1</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0031966#pone-0031966-t002" target="_blank">Table 2</a> respectively. The numbers indicate the classification of the vessel segments according to the Strahler ordering system.</p

General model concept.

<p>The vascular graph model describes the processes occurring in the arteries, arterioles, venules and veins. The alveolus model, a double-continuum approach, represents the processes occurring in the capillary bed and the surrounding tissue (right image according to Terese Winslow).</p

Determination of the permeability tensor for the capillary continuum.

<p>Hexagonal mesh of pulmonary capillaries embedded in a cuboid.</p