Contribution of flow-dependent vasomotor mechanisms to the autoregulation of cerebral blood flow

Abstract

Regulation of cerebral blood flow (CBF) is the result of multilevel mechanisms to maintain the appropriate blood supply to the brain while having to comply with the limited space available in the cranium. The latter requirement is ensured by the autoregulation of CBF, in which the pressure-sensitive myogenic response is known to play a pivotal role. However, in vivo increases in pressure are accompanied by increases in flow; yet the effects of flow on the vasomotor tone of cerebral vessels are less known. Earlier studies showed flow-sensitive dilation and/or constriction or both, but no clear picture emerged. Recently, the important role of flow-sensitive mechanism(s) eliciting the constriction of cerebral vessels has been demonstrated. This review focuses on the effect of hemodynamic forces (especially intraluminal flow) on the vasomotor tone of cerebral vessels and the underlying cellular and molecular mechanisms. A novel concept of autoregulation of CBF is proposed, suggesting that (in certain areas of the cerebrovascular tree) pressure- and flow-induced constrictions together maintain an effective autoregulation, and that alterations in these mechanisms may contribute to the development of cerebrovascular disorders. Future studies are warranted to explore the signals, the details of signaling processes and the in vivo importance of these mechanisms.

Figure 1

Changes in diameter (µm) of an isolated middle cerebral artery and a basilar artery to changes in intraluminal flow as a function of time, redrawn from original traces (P. Toth). In this experimental conditions flow is generated by increasing intraluminal pressure differences (Δ5, Δ10, etc, mmHg) via the vessel by changing the inflow and outflow pressures with the same amount, but in the opposite directions (see details of methods in Toth, P. at al [23]). The opposite diameter responses indicate important regional differences in the nature of flow-induced responses of cerebral arteries. Constriction of middle cerebral artery by increasing cerebrovascular resistance (CVR) contributes to the autoregulation of cerebral blood flow by the “pressure-flow” mechanisms and thereby to the overall regulation of intracranial volume and pressure. In contrast, dilation of the basilar artery to increases in flow, similar to other peripheral vessels contributes to the development of functional hyperemia. See detailed discussion in the text.

Figure 2

Schematic diagram showing the proposed physiological role of flow-induced constriction of cerebral arteries in autoregulation of cerebral blood flow. Combined effect of changes of intraluminal pressure and intraluminal flow (Δ flow) achieves a more effective autoregulation of cerebral blood flow (CBF), whereas only pressure-induced diameter responses still allow substantial increases in CBF, thus inefficient autoregulation. It is likely that in vivo the “plateau” of autoregulation is not perfectly flat, i.e. the gain is less than 1, thus there is a slight increase in CBF as systemic pressure increases. Nevertheless, it is effective enough to prevent an exponential increase of CBF. Also, the range and shape of autoregulatory curve is likely to be more “rounded” at low and high pressure values.

Figure 3

Proposed intracellular and molecular mechanisms eliciting flow-induced responses of cerebral vessels. Flow induces dilation, biphasic responses, or constriction of cerebral vessels depending on the regional and segmental localization of the vessels. We propose that in the internal carotid system larger arteries (such as the middle cerebral artery) constrict to increases in flow. The flow-induced constriction is mediated by 20-hydroxyeicosatetraenoic acid (20-HETE) (a metabolite of arachidonic acid (AA) produced by cytochrome P450 4A enzymes (CYP450 4A) acting via thromboxane A₂/prostaglandin H₂ (TP) receptors and requires COX activity. CYP450 4A also produces reactive oxygen species (ROS), which contribute to the constriction. Whereas, in the brain stem supplied by the vertebro-basilar system larger arteries, such as basilar artery, dilate to flow. Dilation is mediated by NADPH-oxidase (activated by phosphatydilinositol3-kinase (PI3-K) derived H₂O₂ and/or eNOS derived nitric oxide (NO). eNOS is activated in an Akt-dependent pathway, and probably generates H₂O₂, as well (ref number here!! based on Toth at. al, Paravicini at al. and Drouin at al.). The exact nature of signals and sensors are still unknown (see detailed description in the text).