Neurovascular Signaling in the Perivascular Space: Biophysical Principles and Disruption in Hypertension.

The brain's vasculature-from pial arteries through penetrating arterioles and the capillary bed to venous drainage-is enveloped by a narrow, compositionally elaborate perivascular space that provides the primary signaling interface between neural tissue and blood vessels. Here, we advance the principle that the geometry and composition of this space are not constant but change systematically along the vascular tree, and that perivascular space composition at these locations imposes biophysical constraints that dictate the fidelity and gain of neurovascular signaling. We argue that its narrow micro-to-nanodomain geometry, basement membrane sieving effects, and the anionic environment created by heparan sulfate proteoglycans favor small aqueous mediators-potassium, nitric oxide (NO), and adenosine-for rapid, spatially targeted blood flow control, while constraining lipophilic mediators, such as prostaglandins and epoxyeicosatrienoic acids, toward predominantly autocrine action. Reassessing glymphatic fluid flux as a proposed source of vascular mechanical input, we find that the relevant shear forces fall several orders of magnitude below the threshold required to engage canonical smooth muscle mechanotransduction, arguing against a direct mechanical role for perivascular flow. We then synthesize how hypertension degrades each layer of this system: perivascular space expansion dilutes mediator concentrations, barrier breakdown admits plasma proteins capable of sequestering signaling molecules, and inflammation dysregulates the vascular ion channels that serve as signaling effectors. Framing the perivascular space as a biophysically constrained signaling compartment helps reconcile disparate observations of mediator selectivity and fluid mechanics, identifies how its progressive disruption may contribute to cerebrovascular dysfunction associated with chronic hypertension, and may help identify novel targets for preventing or reversing cognitive decline and neurodegeneration.