Cerebrovascular Smooth Muscle Cells as the Drivers of Intramural Periarterial Drainage of the Brain

Abstract

The human brain is the organ with the highest metabolic activity but it lacks a traditional lymphatic system responsible for clearing waste products. We have demonstrated that the basement membranes of cerebral capillaries and arteries represent the lymphatic pathways of the brain along which intramural periarterial drainage (IPAD) of soluble metabolites occurs. Failure of IPAD could explain the vascular deposition of the amyloid-beta protein as cerebral amyloid angiopathy (CAA), which is a key pathological feature of Alzheimer's disease. The underlying mechanisms of IPAD, including its motive force, have not been clarified, delaying successful therapies for CAA. Although arterial pulsations from the heart were initially considered to be the motive force for IPAD, they are not strong enough for efficient IPAD. This study aims to unravel the driving force for IPAD, by shifting the perspective of a heart-driven clearance of soluble metabolites from the brain to an intrinsic mechanism of cerebral arteries (e.g., vasomotion-driven IPAD). We test the hypothesis that the cerebrovascular smooth muscle cells, whose cycles of contraction and relaxation generate vasomotion, are the drivers of IPAD. A novel multiscale model of arteries, in which we treat the basement membrane as a fluid-filled poroelastic medium deformed by the contractile cerebrovascular smooth muscle cells, is used to test the hypothesis. The vasomotion-induced intramural flow rates suggest that vasomotion-driven IPAD is the only mechanism postulated to date capable of explaining the available experimental observations. The cerebrovascular smooth muscle cells could represent valuable drug targets for prevention and early interventions in CAA.

Keywords: Alzheimer's disease; brain; cerebral amyloid angiopathy; lymphatic; multi-scale model; perivascular drainage; poroelastic; vasomotion.

Figure 1

Schematic representation (not to scale) of the IPAD pathways. Soluble Aβ (green dots) and ISF from the brain interstitium enter the BM of capillaries and flow upstream toward large arteries through the BM (dark green) positioned between VSMCs (orange). Transport along the IPAD pathways is shown by the green arrows which are against the direction of arterial pulse and blood flow (red arrow). Three concentric layers of VSMCs are pictured at the larger extreme of the artery, while, for the sake of simplicity, only the outer most layer of VSMCs is shown along the length of the artery. The artery is wrapped in a pial sheath (light purple) and innervated by neurons (blue). At the capillary level, the endothelial BM (light green) is fused with the BM of glia limitans (dark yellow) secreted by astrocytes (yellow); they also interact with brain interstitium (due to gap junctions between the end-feet of astrocytes), allowing entrance of ISF and Aβ in the vascular wall (Morris et al., ; Weller et al., 2018). VSMC, vascular smooth muscle cell; BM, basement membrane; endothelium (red), internal elastic lamina (pink), inner and outer BM (light green), pericyte (purple), and subpial collagen (gray).

Figure 2

Schematic representation (not to scale) of the V-IPAD model. A leptomeningeal artery is modeled as a long thick-walled cylinder with uniform material properties along its length, maintained at a constant intraluminal pressure P and constant longitudinal stretch and exposed to active contractions of VSMCs. The top layer shows the arterial cross section with a layer of BM (green compartment) embedded in the wall (Left) and the longitudinal section of the BM (Right). For simplicity reasons, only one layer of BM is considered at the middle of the wall and the two layers of the VSMCs surrounding the BM are assumed to behave identically. The remaining wall components are not shown, but their effect on the wall elasticity is captured by the radial (σ_r) and circumferential stress (σ_θ). The deformed inner radius, middle radius and outer radius of the arterial wall are denoted by r_i, r_m, and r_o, respectively. The position of the inner layer bounding the BM is assumed at r_m and, owing to stress continuity across the wall, the radial stress σ_r at that point represents the external compressive stress Σ which acts on the BM, i.e., Σ = σ_r(r = r_m); thereby, the arterial wall model is coupled with the BM model. Both r_m and Σ depend on the prescribed vasomotion wave S(z, t) generated by the contractile VSMCs and are determined from the arterial wall model. The position of the outer layer bounding the BM is assumed at r_b with r_b = r_m + 2h, where 2h denotes the whole BM thickness. Since the BM thickness is significantly smaller than the arterial radius, its upper half is assumed to behave identically to its lower half. The deformed thickness h = h(z, t) of the upper-half BM is determined by solving the BM model in the Cartesian system (y, z) and this is justified by the relationship r_b = r_m(z, t) + 2y where 2y ≪ r_m and 2h ≪ r_m. The area delimited by the rectangular is illustrated in the bottom schematic: a sheet of BM modeled as a poroelastic compartment whose fluid-filled pores are squeezed during the VSMC contractions, under the direct actions of −Σ(S(z, t)), driving the fluid out of the BM pores in the direction of the vasomotion wave.

Figure 3

The elastic response of the poroelastic BM. The potential behavior of an idealized “spongy” material is sketched in dotted blue line, while that of the “lymphatic” BM considered throughout this study is plotted in solid red line. (A) The strain energy function W_BM = W_BM(h/H) in the upper (positive) part and the principal Cauchy stress ${\sigma }_e^y={\sigma }_e^y(h/H)$ in the lower (negative) part, as functions of the stretch h/H. The values of h/H (smaller than one) show that the BM thickness is compressed by the normal elastic stress ${\sigma }_e^y$ until reaching the physically-valid lower limit J_*. (B) the stress-permeability relationship, according to which the BM permeability k decreases non-linearly with an increases in the compressive normal stress ${\sigma }_e^y$.

Figure 4

The response of the artery wall to muscular oscillations over one wavelength. (A) The vasomotion wave, (B) the radial position of the BM, and (C) the constrictive stress acting on the BM. Both r_m and Σ depend on S(z, t) and serve as input in the BM model. Progressive change from the red to the green curve shows increase in time; only 4 s from one vasomotion cycle of 10 s are illustrated.

Figure 5

Vasomotion-induced deformation and flows along the BM for three cycles of vasomotion. (A) Oscillations in time of the upper-half thickness of the BM, (B) deformation dependent permeability of the BM, and (C) the corresponding volumetric flow rate along the whole compartment of BM. Progressive change in color from red to magenta shows six distinct spatial points over 750 μm (out of a 2,000 μm wavelength).