Leaky vessels: how the brain deals with pregnancy under pressure.

CHRONIC HYPERTENSION is a major health problem worldwide affecting 25% of the population. Because it is a key risk factor for cerebrovascular disease and stroke and a leading cause of cognitive decline, chronic hypertension has an enormous negative impact on the brain. Episodes of acute hypertension (hypertension emergencies) present an additional array of cerebrovascular and neurological problems. Risk factors for acute hypertension include preexisting chronic hypertension (14). In individuals who are not chronically hypertensive, other causes of acute hypertension include traumatic brain injury, seizures, and severe preeclampsia and eclampsia (5, 14). For example, the cerebrovascular abnormalities seen in a common model of traumatic brain injury are due to acute increases in arterial blood pressure (15). Episodes of acute hypertension in which blood pressure exceeds the autoregulatory capacity of the cerebrovasculature (“breakthrough” of autoregulation) result in marked increases in cerebral blood flow (CBF), increases in microvascular pressure, and disruption of the blood-brain barrier (BBB) (6, 8, 10, 11). Clinically, this sequela underlies hypertensive encephalopathy, a condition characterized by headache, seizures, and other neurological symptoms including cerebral edema. The effectiveness of autoregulation and the loss of BBB integrity during large acute increases in arterial pressure exhibit regional and segmental differences and can change in disease (8, 10, 11). This heterogeneity results from a variety of factors including differences in vascular structure, intrinsic functional properties of blood vessels (mainly at the level of vascular muscle), as well as modulation of autoregulatory responses by endothelial cells, potassium channels in vascular muscle, and extrinsic perivascular innervation by sympathetic, parasympathetic, and sensory neurons (6). As a result, there are regional differences in local hemodynamics including increases in microvascular pressure in capillaries and veins (8, 10). Regional differences in disruption of the BBB during acute hypertension are not due to inherent differences in properties of the BBB but rather arise because of differences in the magnitude of increases in microvascular pressure (8, 10, 11). Molecular changes that underlie increases in BBB permeability at the level of the endothelial cell include alterations in cell surface charge, density of caveolae, phosphorylation of tight junction proteins, and the actin-myosin cytoskeleton (12). Vascular remodeling represents a three-dimensional rearrangement of the vessel wall around its lumen (2). When accompanied by changes in the cross-sectional area of the lumen, inward or outward vascular remodeling has major effects of vascular resistance and the transmission of blood pressure down the vasculature (Fig. 1). Inward remodeling of cerebral arteries and arterioles occurs in some forms of chronic hypertension (2, 3). This type of remodeling protects the distal microcirculation from full transmission of elevated blood pressure and thus attenuates vascular dysfunction, increases in microvascular pressure, and increases in permeability when local pressure rises (Fig. 1). Such a mechanism protects the BBB during acute hypertension in chronically hypertensive animals (11). Although large elevations in blood pressure are a key feature of severe preeclampsia and eclampsia, relatively little is known regarding the effects of acute hypertension on the cerebral circulation during pregnancy (5). In this issue of the Journal of Applied Physiology, Cipolla et al. (7) describe a series of studies addressing the hypothesis that changes in the cerebral vasculature during normal pregnancy result in the brain being predisposed to vascular injury during acute hypertension. In those studies, a variety of Address for reprint requests and other correspondence: F. M. Faraci, Dept. of Internal Medicine, Div. of Cardiovascular Diseases, E318-2 GH, Univ. of Iowa, Carver College of Medicine, Iowa City, IA 52242-1081 (e-mail: [email protected]).