PIP2 as the “coin of the realm” for neurovascular coupling

Abstract

Cerebral small vessel diseases (SVDs) are a group of related pathologies that collectively account for over 25% of ischemic strokes and more than 40% of all dementias (1, 2). Although genetic forms have been identified, sporadic SVDs are the most common and become prevalent with increasing age. The causes of sporadic SVDs remain poorly understood, and no treatment options are currently available. SVDs can occur in any organ in the body. However, the brain’s microvasculature is uniquely susceptible to dysfunction. In tissues such as skeletal muscle, metabolic demand is met in part by an organ-wide dilation of the vasculature that lowers the resistance to flow so that increased demand is satisfied by a surge of blood flow throughout the tissue. In contrast, the skull imposes an essentially fixed volume to prevent global increases in the amount of blood in the brain. Thus, nature has evolved mechanisms unique to the cerebral circulation to rapidly redirect blood flow to brain regions with higher metabolic activity at the cost of diminished flow elsewhere (3, 4). This process is termed functional hyperemia. It involves communication between active brain regions and the cerebral vasculature by loosely defined processes known as “neurovascular coupling” (5–7). Neurovascular coupling is disrupted in cerebral SVDs (1, 2), and the diminished state of functional hyperemia contributes to vascular cognitive impairment and dementia. In PNAS, Dabertrand et al. (8) demonstrate the molecular basis for the loss of functional hyperemia for a particular SVD and, impressively, show how the dysfunction may be reversed. In particular, impaired functional hyperemia is rescued by exogenously supplying the minor phospholipid, phosphatidylinositol 4,5-bisphosphate (PIP2), to a mouse model of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) (9). This is the predominant genetic SVD and a model for more common sporadic forms of SVD. The findings by Dabertrand et al. (8) may set the stage for the development of treatments for impaired neurovascular coupling and dementias associated with cerebral SVDs. The vasculature of the brain is organized as a hierarchy (10). The pial arteries form a highly interconnected network that spans the surface of the cortex. Dynamic changes in the diameter of different branches allow the pia to shuttle blood to areas of acute metabolic need (11). This network sources penetrating arterioles that dive into the parenchyma and, in turn, supply a vast, interconnected network of capillaries that provide energetic substrates to all brain cells. Despite the great numbers of paths for blood cells to take as they journey from a penetrating arteriole to their eventual exit through a penetrating venule and then vein, the capillaries provide the greatest resistance to flow in the brain (12). An emerging model of functional hyperemia in the brain focuses on the capillaries. While the density of the capillary network varies between different regions of the brain, the typical distance from a location in the neocortical parenchyma to the nearest capillary is quite small, about 13 μm (13). Drawing on this implicit, intimate relation between neurons and capillaries, Longden et al. (14) hypothesized that the brain uses the capillary network as a sensory web to detect elevated neuronal activity and subsequently signal upstream penetrating arterioles and pial arteries to dilate. The mechanism involves K ions and the inwardly rectifying K channel Kir2.1 (Fig. 1). Potassium ions are released during every neuronal action potential, and in principle, the local [K] can approach 10mM in the vicinity of capillaries (14, 15). This concentration is sufficient to activate Kir2.1, whose threshold for opening is raised by the increase in extracellular [K]. This leads to the onset of a regenerative, hyperpolarizing pulse that propagates to adjacent endothelial cells via gap junctions, thereby stimulating further Kir2.1 channel activity to spread the signal. Upon reaching upstream arterioles, this hyperpolarizing signal is conveyed