Neurovascular signaling in the brain and the pathological consequences of hypertension 1 2

7 The execution and maintenance of all brain functions are dependent on a continuous flow of 8 blood to meet the metabolic needs of the tissue. To ensure the delivery of resources required for neural 9 processing and the maintenance of neural homeostasis, the cerebral vasculature is elaborately and 10 extensively regulated by signaling from neurons, glia, interneurons, and perivascular nerves. 11 Hypertension is associated with impaired neurovascular regulation of the cerebral circulation and 12 culminates in neurodegeneration and cognitive dysfunction. Here, we review physiological processes of 13 neurovascular signaling in the brain and discuss mechanisms of hypertensive neurovascular dysfunction. 14 15 Introduction 16 The brain has a high basal metabolic rate and limited capacity to store energy. As a result, the 17 execution and maintenance of all brain functions are dependent on a continuous flow of blood that is at 18 all times and under all conditions sufficient to meet the metabolic needs of the tissue. The cerebral 19 vasculature, as the infrastructure by which the brain receives the resources necessary to support neural 20 processing and maintain the milieu necessary for neural homeostasis, is elaborately and extensively 21 regulated by signaling from neurons, glia, interneurons, and perivascular nerves. 22 The brain is particularly vulnerable to hypertensive injury. Hypertension leads to 23 neurodegeneration and cognitive disability, and has been causally linked to dementia and Alzheimer’s 24 disease (AD) (23, 64). It is increasingly evident that hypertensive neurodegeneration is a consequence 25 Articles in PresS. Am J Physiol Heart Circ Physiol (October 25, 2013). doi:10.1152/ajpheart.00364.2013 Copyright © 2013 by the American Physiological Society. 2 of the damaging effects of high blood pressure on the cerebral vasculature. Chronic and even acute 26 exposure to elevated intravascular pressure sets in motion a number of pathological mechanisms that 27 disrupt neurovascular regulation of cerebral blood flow (CBF). To understand how these mechanisms 28 interfere with neurovascular signaling in the brain, the physiological mechanisms of these processes 29 must first be understood. In this review, we provide an overview of neurovascular signaling in the brain 30 and discuss mechanisms of hypertensive neurovascular dysfunction. 31 32 Neurovascular regulation of cerebral blood flow 33 Anatomy of the cerebral circulation 34 The cerebral vasculature consists of pial arteries located at the base and on the surface of the 35 brain and their downstream tributaries. Pial arteries branch and narrow into pial arterioles, which also 36 run along the brain surface. Pial arteries and arterioles are innervated by nerve fibers arising from the 37 superior cervical, sphenopalatine/otic, and trigeminal ganglia (67). At various points, pial arteries and 38 arterioles form perpendicular branches that dive from the surface parent artery into the brain 39 parenchymal tissue, called “parenchymal arterioles” (also referred to as “penetrating arterioles”). The 40 point of entry of the arteriole into the brain parenchyma is surrounded by a small, cerebral spinal fluid 41 (CSF)-filled pocket called the Virchow-Robin space. Innervation by extrinsic nerve fibers terminates at 42 the Virchow-Robin space, beyond which parenchymal arterioles are directly contacted, or “innervated”, 43 by glial and neuronal cell types. Parenchymal arterioles are predominantly surrounded by “endfoot” 44 terminals of astrocyte projections, but there is evidence to suggest they are also contacted directly by 45 interneurons (24, 173). Brain capillaries are enveloped by astrocytic endfeet as well, with pericytes 46 occasionally interposed between the endfoot and the capillary wall. Neurovascular regulation of CBF 47 occurs primarily at pial arteries and parenchymal arterioles; however, neurovascular signaling through 48 contractile pericytes has been suggested to regulate capillary diameter as well (53, 68). 49