**Abstract**

This chapter summarizes the current knowledge regarding the regulation of the tone of cerebral resistance arteries under conditions of normal health and with the development of chronic diseases (e.g., metabolic disease). The work integrates the myogenic (pressure-induced) regulation of vascular tone, the impact of elevated luminal flow or shear stresses, that of local tissue metabolic activity on vascular tone and the concept of neurovascular coupling (linking neuronal activity to the impacts on vascular diameter). In addition, this work summarizes some of the recent work on how diseases such as type 2 diabetes impact the mechanisms of cerebrovascular tone regulation. It is anticipated that the current review will provide the reader with an up-to-date understanding of how the cerebral resistance vessels respond to changes in their local environment and contribute to the regulation of blood flow within the brain.

**Keywords:** cerebral, perfusion resistance, metabolic disease, vascular function, vascular disease risk

## **1. Introduction**

The brain has a remarkably high metabolic rate and thus requires a highly disproportional amount of blood flow. Although its only 2% of body weight, the brain takes up 15–20% of cardiac output [1], making it one of the most highly perfused organs in the human body. This high metabolic rate coupled with its limited capacity for energy storage [2] necessitates heavy reliance on oxidative metabolism and thus requires constant blood flow to maintain nutrient and oxygen supply, remove waste products, and maintain a state of cerebral metabolic homeostasis. Severe underperfusion can quickly result in unconsciousness [3] and if prolonged, death [4]; while chronic mild under perfusion is associated with cognitive decline [5]. In addition to its high perfusion and metabolic rate, the cerebral circulation faces a unique challenge of being enclosed in the skull. This rigid structure prevents the expansion of tissue and extracellular fluid. Swelling within the skull from vasogenic edema leads to an increase in intracranial pressure which in turn can lead to neurologic complications or in more extreme cases death [1]. The unique challenges of the cerebral circulation, including intolerance to ischemia and edema, coupled with the paramount importance of maintaining constant nutrient and oxygen supply to cerebral tissue creates a need for precise regulation of cerebral blood flow and therefore the presence of redundant intrinsic mechanisms for its regulation. The anatomy of the brain vasculature ensures multiple routes for blood and oxygen delivery potentially allowing for perfusion even in cases of a blocked blood vessel [6]; however, acute

regulation of flow is done primary by altering the diameter of blood vessels, and thus the resistance to flow. The major mechanisms of local regulation of vascular tone intrinsic to the cerebral vasculature include myogenic, shear, and metabolic based regulation. Although each mechanism has a discrete effect on vascular tone the integration of the different contributors to determine an appropriate level of tone is much more difficult to discern, especially in the cerebral circulation. These complex interactions allow for highly accurate control of cerebral blood flow in addition to protecting vulnerable downstream capillaries from high pressures and flow rates that could otherwise lead to edema; but, they also introduce several potential areas for failure. The intimate interactions of the various mechanisms of regulation of flow mean that the failure of one mechanism has the potential to initiate a cascade of events that results in inappropriate regulation of flow. As such abnormal execution of vascular tone regulation may form the basis of vascular pathologies [7].

One of these pathologies with a significant vascular component associated with impaired cerebral vascular tone regulation is metabolic syndrome (MetS). The incidence and prevalence of MetS is growing in Western society [8–10] and is contributing to decreased quality of life and increased economic burden. Thus an understanding of how it alters the cerebral circulation is crucial. MetS is categorized by a collection of metabolic risk factors including obesity, hypertension, atherogenic dyslipidemia and impaired glycemic control creating a pro-oxidant pro-inflammatory environment that raises the risk of developing impaired vascular structures and function [11–14]. These impairments are particularly detrimental when they affect the cerebral circulation and lead to cerebrovascular pathologies such as stroke or transient ischemic attack (TIA) due to the detrimental consequences associated with such events. However, cognitive impairments are not limited to individuals that have experienced an acute ischemic event since even in their absence MetS is strongly associated with impaired cognitive function and decreased quality of life [15–18]. Therefore preventing their occurrence by protecting the cerebrovasculature from functional and structural decline is paramount. This chapter will present a description of the local mechanisms involved in the regulation of cerebral vascular tone, how they integrate with one another and how they can be compromised in disease. Although impairments to the regulation of cerebral vascular tone are not limited to conditions associated with MetS this discussion will focus on the impact of MetS and its associated risk factors.
