Chronic social isolation in the prairie vole induces endothelial dysfunction: implications for depression and cardiovascular disease

Abstract

Humans with depression show impaired endothelium-dependent vasodilation, one recent demonstration of which was in the form of a reduced acetylcholine (ACh)-induced relaxation of adrenergically-precontracted small arteries biopsied from older depressed patients. Results from such uses of ACh in general have been validated as the most predictive marker of endothelium-related cardiovascular diseases. Accordingly, we examined vascular reactivity to ACh in the socially isolated prairie vole, a new animal model relevant to human depression and cardiovascular disease. Thoracic aortas were carefully dissected from female prairie voles after one month of social isolation (versus pairing with a sibling). Only aortas that contracted to the adrenergic agent phenylephrine (PE) and then relaxed to ACh were evaluated. Among those, ACh-induced relaxations were significantly reduced by social isolation (p<0.05), with maximum relaxation reaching only 30% (of PE-induced precontraction) compared to 47% in aortas from paired (control) animals. Experimental removal of the endothelium from an additional set of aortic tissues abolished all ACh relaxations including that difference. In these same tissues, maximally-effective concentrations of the nitric oxide-donor nitroprusside still completely relaxed all PE-induced precontraction of the endothelial-free smooth muscle, and to the same degree in tissues from isolated versus paired animals. Finally, in the absence of PE-induced precontraction ACh did not relax but rather contracted aortic tissues, and to a significantly greater extent in tissues from socially isolated animals if the endothelium was intact (p<0.05). Thus, social isolation in the prairie vole may 1) impair normal release of protective anti-atherosclerotic factors like nitric oxide from the vascular endothelium (without altering the inherent responsiveness of the vascular smooth muscle to such factors) and 2) cause the endothelium to release contracting factors. To our knowledge this is the first demonstration of this phenomenon in an animal model of depression induced solely by social isolation. These findings have implications for understanding mechanisms involved in depression and cardiovascular disease.

Social networks, social support, and burden in relationships, and mortality after breast cancer diagnosis in the Life After Breast Cancer Epidemiology (LACE) Study

“…In long-term breast cancer survivors, social networks may still be important for non-breast cancer specific causes, most notably cardiovascular disease. Since breast cancer treatments can be cardiotoxic, it is possible that social relationships may help protect against adverse cardiovascular effects, through oxytocin-mediated reductions in cardiovascular reactivity[21, 22], reductions in inflammation[23–26] effects on endothelial function[27], the cardiovascular benefits of buffering of stress[28], and increased physical activity related to social participation.…”

Loneliness Across Phylogeny and a Call for Comparative Studies and Animal Models

“…T. Cacioppo, Hawkley, Crawford, et al, 2002) and during the course of a normal day (Hawkley, Burleson, Berntson, & Cacioppo, 2003). Consistent with this effect in humans, research in socially isolated, compared with socially housed, prairie voles indicates that chronic isolation of these typically monogamous animals induces alterations in cellular functioning in the vasculature (e.g., the release of vascular contracting factors in endothelial cells) that contribute to higher levels of vascular resistance (Peuler, Scotti, Phelps, McNeal, & Grippo, 2012). …”

Resveratrol can both enhance and relax adrenergic contractions of the rat tail artery

“…1, a maximum of eight rings were selected at random from the middle portion of each segment for experimental treatments during each experimental period. Each ring was mounted between two tungsten wire stirrups, which in our experience (20,21,22,23, 25) are strong enough not to bend during ring contractions yet thin enough not to damage the inner endothelial cell layer [presence of intact endothelium was confirmed by relaxation responses to acetylcholine in a representative number of precontracted rings in preliminary and follow-up experiments]. Each ring was then suspended in a 40 ml tissue bath and allowed to equilibrate for several minutes before experimentation at a passive loading (resting) tension of 1,500 mg in standard physiological (Krebs) buffer which was warmed to 37 °C and gassed to pH 7.4 with regulated delivery of O 2 /CO 2 .…”

“…We chose an alpha adrenergic receptor agonist because of the widely recognized importance of adrenergic vasoconstrictor support of arterial pressure in vivo . We chose the smooth muscle selective alpha-1 agonist phenylephrine (PE) for that purpose because 1) it has already been repeatedly employed successfully by other resveratrol investigators in other arteries (12, 15) and 2) as we have discussed previously (25) it produces more sustained precontractions than other agonists previously used in other resveratrol studies (e.g. high potassium buffer or the nonselective adrenergic agonist norepinephrine) (13, 16).…”