Central and Peripheral Mechanisms of T-Lymphocyte Activation and Vascular Inflammation Produced by Angiotensin II–Induced Hypertension

Abstract

T he CNS plays an integral role in blood pressure regulation, primarily through sympathetic activation and mediation of various neurohumoral factors such as angiotensin II (Ang II) and vasopressin. [1][2][3][4] Hormones such as these can access the circumventricular organs, which are adjacent to the cerebral ventricles and have a poorly formed blood brain barrier. The circumventricular organs implicated in blood pressure control include the organum vasculosum of the lamina terminalis (OVLT), the area postrema, the subfornical organ, and the anteroventral third ventricle (AV3V) region. 5 The AV3V region includes the median preoptic nucleus, the OVLT, and the periventricular nucleus and has been shown to play an important role in several behavioral, neural and hormonal functions involved in body fluid and cardiovascular homeostasis. 6,7 Electrolytic lesions that disrupt the AV3V region have been shown to abolish virtually all of the central actions of Ang II, including drinking behavior, sympathetic outflow, and vasopressin release. 6 Electrolytic lesions of this brain region abolish the centrally mediated pressor response to central and peripheral infusions of Ang II, as well as preventing and/or reversing several other forms of experimental hypertension. 5,6 In addition to central mechanisms, substantial evidence suggests that inflammation can contribute to the pathophysiology of hypertension. For example, inflammatory cells accumulate in the kidney and vasculature of hypertensive animals, and the prevention of this can lower blood pressure. 8 Recently, our laboratory has found that mice lacking T-lymphocytes are resistant to the development of both Ang II and DOCA-salt induced hypertension. 9 Adoptive transfer of T, but not B cells restored hypertension in these animals. Despite the growing evidence for the role of T cells in hypertension, the mechanisms underlying T-cell activation and vascular infiltration by T cells remain unclear. Given the importance of the CNS in regulating blood pressure, we hypothesized that the CNS could Original

Myocardial migration by fibroblast progenitor cells is blood pressure dependent in a model of angII myocardial fibrosis

“…Hydralazine was chosen based on its antihypertensive properties of lowering blood pressure in a dose-dependent manner without acting on AngII receptors. 24,25 RAS upregulation was demonstrated in the animals that received AngII+hydralazine, as evidenced by a significant elevation in serum aldosterone, which is a downstream mediator and marker of RAS activation. Our primary observation using this model was that the addition of hydralazine to AngII resulted in normalization of the blood pressure and inhibition of the fibrosis that is normally seen in animals receiving AngII.…”

“…Our findings are in keeping with other studies that have suggested that the effects of AngII on fibrosis are blood pressure dependent. 24,25,39 Some reports have even suggested that blood pressure can affect the migration of fibrocytes (CD45 + /SMA + ) into the myocardium, but these reports did not elucidate a definitive mechanism. 25 In contrast, transgenic mice that overexpress the AT1a receptor and develop hypertrophy and fibrosis do so without developing hypertension, emphasizing the multifactorial pathways capable of promoting extracellular matrix deposition and fibrosis.…”

Immune Mechanisms in Arterial Hypertension

“…The sympathetic nervous system innervates both primary (thymus, bone marrow) and secondary tissues and lymphoid tissues (spleen, lymph nodes), and most immune cells express receptors for neurohormones and catecholamines. 16 Inhibition of the NADPH oxidase subunit p22 phox in the subfornical organ eliminated the Ang II-induced hypertensive response and vascular inflammation. 17 In addition, a peripheral neuroimmune response in the spleen, mediated by celiac ganglion efferent nerve fibers, is essential for the development of hypertension.…”

The sympathetic nervous system and blood pressure in humans: implications for hypertension

“…88,123,124 T-lymphocytes appear particularly critical for Ang II and deoxycorticosterone acetate-salt-induced hypertension and the concomitant vascular and kidney dysfunction. 121,122,125 T-cell activation is increased by Ang II and leads to the production of pro-inflammatory cytokines. 121 Intriguingly, anti-TNFa therapy (etanercept) has been shown to prevent Ang II-induced hypertension and vascular oxidative stress.…”