Early life stress downregulates endothelin receptor expression and enhances acute stress-mediated blood pressure responses in adult rats

Abstract

We hypothesized that early life stress enhances endothelin (ET-1)-dependent acute stress responses in adulthood. We utilized a unique rat model, wildtype (WT) and ETB receptor-deficient spotting lethal (sl/sl) rats, as well as pharmacological blockade of ET receptors, in a model of early life stress, maternal separation (MS). MS was performed in male WT and sl/sl rats 3 h/day from day 2 to 14 of life. Acute air jet stress (AJS)-induced responses (elevation in blood pressure, plasma corticosterone, and plasma ET-1) were evaluated in adult MS rats compared with the nonhandled littermate (control) rats. MS significantly augmented the acute AJS-induced blood pressure response (area under the curve) in WT rats compared with control, while the AJS-induced pressor responses were similar in sl/sl MS and control rats. ET receptor blockade significantly blunted the AJS-induced pressor response in WT MS and control rats. Moreover, AJS-induced plasma corticosterone levels in control rats were sensitive to ET receptor blockade, yet, AJS did not alter plasma corticosterone levels in MS rats. MS significantly increased circulating ET-1 levels, and AJS-induced plasma ET-1 levels were similarly increased in control and MS rats. MS induced a significant downregulation in expression of ETA and ETB receptors in aortic tissue compared with control rats. These results indicate that early life stress reduced expression of ETA and ETB receptors, leading to alterations in the ET pathway, and an exaggerated acute stress-mediated pressor response in adulthood.early life stress; maternal separation; air jet stress; blood pressure; endothelin; corticosterone IN HUMANS, THERE IS A LARGE body of epidemiological evidence that early social experiences can promote phenotypic changes that persist in adult life (5,12,28). An adverse environment during early life increases the susceptibility to develop heart disease, as well as depression, drug abuse, obesity, and diabetes (21,24,32).Acute behavioral stress responses in adult life are influenced by early life maternal care in both humans (53) and rodents (36). Maternal separation is a widely used animal model of early life stress and chronic behavioral stress (20). Rat pups separated from their mothers daily for a prolonged period (up to 3 h) during the hyporesponsive period display abnormal anxiety-related behavior (41, 43), as well as increased acute behavioral and endocrine stress reactivity as adults (4,27,38,44).Individuals with increased susceptibility to stressors may also have an exacerbated rise in blood pressure (26). Acute stressors induce many physiological responses, and greater reactivity to stress or delayed poststress recovery predicts future cardiovascular disease risk (7), such as stroke (14), hypertension (37), and preclinical atherosclerosis (23,52). An acute stress-induced rise in blood pressure results from autonomic and neuroendocrine-mediated changes in cardiac contractility and peripheral vascular resistance (18). Particularly relevant to this study, acute stress is associa...

Acute Pressor Response to Psychosocial Stress Is Dependent on Endothelium‐Derived Endothelin‐1

“…Consistent with prior studies in humans and rats,2, 11, 12, 13, 14, 15, 16, 20, 21 flox mice exhibited a significant increase in plasma ET‐1 in response to CSS, whereas VEETKO mice exhibited no change in plasma ET‐1 following CSS. We found that pulmonary ET receptor expression and affinity are similar in VEETKO and flox mice, suggesting no differences in ET‐1 clearance capacity in VEETKO and flox mice.…”

“…D'Angelo et al found that ABT‐627 potentiates the pressor response to air jet stress in ET B receptor–deficient rats and transgenic controls on a high‐salt diet50 and in Dahl salt‐resistant, but not Dahl salt‐sensitive, rats,51 suggesting that the ET A receptor may function to attenuate sympathetic responses differentially in these rat strains. More important, the CSS paradigm is distinct from restraint air jet stress in that CSS elicits a prolonged pressor response, for >1 hour, and restraint air jet stress produces a pressor response that dissipates in minutes 21, 46. Together, these studies suggest a complex role of the ET A receptor in the pressor response to acute psychosocial stress paradigms.…”

“…In population studies, psychosocial risk factors were associated with elevated plasma ET‐1 levels,17, 18 and acute psychosocial stress‐induced acute coronary syndrome was associated with a robust elevation in plasma ET‐1 levels 19. In rodents, experimental acute psychosocial stress, in the form of restraint with air jet stress, leads to an increase in plasma ET‐1 levels in both wild‐type and prehypertensive rats 20, 21. Despite these studies, the cellular source of stress‐induced plasma ET‐1 remains unclear, because this ET‐1 could be derived from the vascular endothelium, immune cells, neuronal cells, or other potential cellular sources.…”

Antisense versus proopiomelanocortin mRNA reduces vascular risk in a murine model of type-2 diabetes following stress exposure in early post-natal life

“…According to present data, and data in the literature, we retain that at least three different mechanisms can concur in producing functional artery alteration: (1) post-natal handling reduces endothelial nitric oxide synthase buffering capacity, thus sensitizing adult rodents to angiotensin II-induced hypertension [20][21][22]33]; (2) hyperglycemia contributes to cardiovascular diseases, as confirmed by studies carried out on both diabetic and non-diabetic patients, and on animal models [12,15,19]; (3) elevation of plasma ACTH and corticosterone produces vascular alterations and hypertension, as it was reported following chronic treatment with corticosteroids and with corticotrophin (ACTH and analogues) in adult animals [23,35,36].…”

“…Clinical-epidemiological investigations found connection between adverse childhood experiences and the risk for developing metabolic and cardiovascular conditions in the adult age in humans [1,7,27,32]. It has been shown also that postnatal psychological stress models were followed by vascular and renal dysfunction in adult rats [20,33]. It is therefore of importance to have simple, reliable and inexpensive models to study the evolution of "pre-diabetic status" up to the appearance of "complications status", in order to understand etiopathogenetic mechanisms, and to develop drugs useful to prevent or reduce risk of complications.…”