Regional Blood Flow in the Normal and Ischemic Brain Is Controlled by Arteriolar Smooth Muscle Cell Contractility and Not by Capillary Pericytes

Abstract

Summary The precise regulation of cerebral blood flow is critical for normal brain function and its disruption underlies many neuropathologies. The extent to which smooth muscle-covered arterioles or pericyte-covered capillaries control vasomotion during neurovascular coupling remains controversial. We found that capillary pericytes in mice and humans do not express smooth muscle actin and are morphologically and functionally distinct from adjacent precapillary smooth muscle cells (SMCs). Using optical imaging we investigated blood flow regulation at various sites on the vascular tree in living mice. Optogenetic, whisker stimulation or cortical spreading depolarization caused microvascular diameter or flow changes in SMC but not pericyte-covered microvessels. During early stages of brain ischemia, transient SMC but not pericyte constrictions were a major cause of hypoperfusion leading to thrombosis and distal microvascular occlusions. Thus, capillary pericytes are not contractile and regulation of cerebral blood flow in physiological and pathological conditions is mediated by arteriolar smooth muscle cells.

What is a pericyte?

“…4,5 This has made pericytes an important therapeutic target. 6,7 Paradoxically, a recent paper 8 dismissed the idea that pericytes are involved in the regulation of brain blood flow, despite confirming all the results of earlier work showing a role for pericytes. How can these conclusions be reconciled?…”

“…26). 8 This was inevitable: if all contractile pericytes are re-defined to be smooth muscle cells, it has to be the case that the dilations are produced by ''smooth muscle cells'' and not pericytes. Nevertheless, the cells producing the dilations in the study of Hill et al 8 and in earlier work 3,4 are identical.…”

“…8 This was inevitable: if all contractile pericytes are re-defined to be smooth muscle cells, it has to be the case that the dilations are produced by ''smooth muscle cells'' and not pericytes. Nevertheless, the cells producing the dilations in the study of Hill et al 8 and in earlier work 3,4 are identical. Indeed, when examining the branching order of capillaries, with branch order 0 being the penetrating arteriole, 1 being the first capillary (sometimes termed a pre-capillary arteriole) coming off that, and so on, Hill et al 8 found that their a-SMA reporter was expressed in pericytes down to at least the second order capillary in nearly 60% of cases, and in higher branch order capillaries in 30% of cases (see Figure 4K of their paper which shows a-SMA labelling on spatially separated pericytes along capillaries).…”

Neuronal networks and mediators of cortical neurovascular coupling responses in normal and altered brain states

“…Additionally, changes in microdomains of the microcirculation should be better explored, as both constriction and dilation are likely to occur to generate the final integrated haemodynamic response [174,175]. In view of recent findings [130][131][132]176], the exact role of astrocytes and pericytes, and the extent and timescale of their contribution in the haemodynamic responses need clarification. Finally, the impact of acute and chronic loss or gain of neuronal function, as seen in physiological and pathological conditions, and of a compromised cerebral circulation, as seen in cardiovascular diseases, vascular dementia and Alzheimer's disease, on the neurovascular unit and its function needs further work to better understand pathological brain imaging data.…”

Interpreting BOLD: towards a dialogue between cognitive and cellular neuroscience

“…Classically blood flow was thought to be regulated solely by rings of smooth muscle on penetrating arterioles, but recent work has suggested that capillary blood flow can also be regulated by virtue of the contraction and relaxation of pericytes [49,50]. While these findings are somewhat disputed [51,52], this is primarily due to differences in the definitions of capillaries, arterioles, smooth muscle cells and pericytes (see [53] and Uhlirova et al [4] in this issue). In fact, the studies broadly agree that cerebral blood vessels from large to small calibre (down to 4 mm) and even up to four branches from diving arterioles can be regulated by neuronal activity [50,52] due to the relaxation of vascular mural cells which express contractile proteins, including those that have a 'bump on a log' morphology and processes extending along and around the blood vessels [52,54].…”