PIP2 as the "coin of the realm" for neurovascular coupling.

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 … [↵][1]1To whom correspondence may be addressed. Email: searley{at}med.unr.edu. [1]: #xref-corresp-1-1