Involvement of endothelial-derived relaxing factors in the regulation of cerebral blood flow

Abstract

Despite numerous researches and advances in the present times, delayed cerebral vasospasm remains a severe complication leading to a high mortality and morbidity in patients with subarachnoid hemorrhage (SAH). Since the discovery of endothelium-derived relaxing factor (EDRF) in 1980, its role in delayed cerebral vasospasm after SAH has been widely investigated as well as in regulation of basic cerebral blood flow, pathophysiology of vasoconstriction and application on prevention and treatment of cerebral vasospasm. Among all the EDRFs, nitric oxide has caught the most attention, and the other substances which display similar properties with characteristics of EDRF such as carbon monoxide (CO), hydrogen sulfide (H(2)S), hydrogen peroxide (H(2)O(2)), potassium ion (K(+)) and methane (CH(4)) have also evoked great interest in the research field. This review provides an overview of recent advances in investigations on the involvement of EDRFs in the regulation of cerebral blood flow, especially in cerebral vasospasm after SAH. Possible therapeutic measures and potential clinical implications for cerebral vasospasm are also summarized.

The Potential Role of Hydrogen Sulfide in the Regulation of Cerebrovascular Tone

“…The first identified gasotransmitter molecule in the mammalian circulation was NO [16] which was shown to increase cerebral blood flow by decreasing vascular resistance in the cerebral vessels similarly to its effects in the systemic circulation [17]. NO in the central nervous system may originate from endothelial cells (produced by endothelial NOS, eNOS), from autonomic nitrergic nerve endings or from neurons of the central nervous system (produced by neuronal nitric oxide synthase, nNOS), or by the inducible isoform of the enzyme (iNOS) [17,18]. Decreased availability of NO is known to be a triggering factor of vasospasm after subarachnoid hemorrhage, whereas overproduction through iNOS occurs during inflammation or cerebral ischemia [18].…”

“…NO in the central nervous system may originate from endothelial cells (produced by endothelial NOS, eNOS), from autonomic nitrergic nerve endings or from neurons of the central nervous system (produced by neuronal nitric oxide synthase, nNOS), or by the inducible isoform of the enzyme (iNOS) [17,18]. Decreased availability of NO is known to be a triggering factor of vasospasm after subarachnoid hemorrhage, whereas overproduction through iNOS occurs during inflammation or cerebral ischemia [18]. Several evidences provided by experiments involving animals indicate that the NOS enzyme contributes to the neurovascular coupling (known as functional hyperemia) and a recent study demonstrated this in humans as well [15,19].…”

“…Subsequently, it was realized that not only NO but other endogenously produced molecules such as carbon monoxide (CO) can also play a role in the regulation of cerebrovascular system [20]. Endogenously produced CO originates from the metalloprotein heme by its synthesizing enzyme, heme oxygenase (HO), which has two distinct isoforms, the inducible HO-1 and the constitutive HO-2 [18,21]. The production of CO in the central nervous system takes place in the cerebral vascular cells, neurons and glial cells by HO-2, which has the highest concentration in the brain [22].…”

Cyclic ADP-Ribose and NAADP in Vascular Regulation and Diseases

“…Another important mechanism regulating vascular tone is the production of endothelium-derived relaxing factors (EDRFs), where blood vessels, particularly arteries, can produce relaxation in response to blood flow, shear stress and circulatory vasodilators, which may importantly contribute to the control of vascular tone under physiological or pathological conditions (Edwards et al, 2010; Qi et al, 2011; Vanhoutte et al, 2009). It is well known that Ca 2+ activation of ECs is critically implicated in the production of EDRFs such as nitric oxide (NO), epoxyeicosatrienoic acids (EETs) and prostacyclins (Yi et al, 2002; Zhang et al, 2005; Zhang et al, 2004).…”

Traumatic Brain InjuryIn VivoandIn VitroContributes to Cerebral Vascular Dysfunction through Impaired Gap Junction Communication between Vascular Smooth Muscle Cells

“…8 These and other aspects of normal cerebral vascular function are described in detail in numerous reviews. [9][10][11][12][13][14][15][16] Traumatic brain injury (TBI) impairs or abolishes many cerebral vascular compensatory responses in humans and experimental animals. 9,[17][18][19] Increased vulnerability to secondary insults may be due, in part, to traumatic cerebral vascular injury resulting in impaired compensatory responses to changes in levels of arterial blood pressure, carbon dioxide, oxygen, and so on.…”