Impaired vascular function in mice with an active cytomegalovirus infection

Abstract

Human cytomegalovirus (CMV) is implicated in vascular complications through endothelial dysfunction. However, the effect of in vivo infections on vascular function in isolated arteries has not been examined. In pregnancy, systemic and uterine vascular adaptations accommodate increased blood volume through several mechanisms, including decreased sensitivity to vasoconstrictors and increased production of endothelial-dependent vasodilators. We hypothesized that an active in vivo CMV infection would reduce vasodilation of isolated arteries to the endothelial-dependent vasodilator methacholine and increase vasoconstriction to the alpha(1)-adrenergic receptor agonist phenylephrine and that these CMV-induced changes would be accentuated in late pregnancy. A mouse CMV infection model was used to study vascular responses in isolated mesenteric and uterine arteries from nonpregnant and late pregnant mice. In the mouse, CMV is not transmitted to the fetus. Accordingly, there was no evidence of active infection in any fetus examined, even though an active infection was found in salivary glands, uterine and mesenteric arteries, and placentas. Contrary to our hypothesis, increased endothelial-dependent vasodilation was found in mesenteric arteries from infected compared with uninfected nonpregnant and pregnant mice These data implicate active CMV infections in hypotensive disorders. Similarly, increased vasodilation was found in uterine arteries from infected vs. uninfected nonpregnant mice. However, this was completely reversed in infected compared with uninfected late pregnant mice in which vasodilation in uterine arteries was significantly reduced. Uterine arteries from infected pregnant mice also showed increased vasoconstriction to phenylephrine. Maternal infection led to decreased placental weights but had no effect on fetal weights in late pregnancy. These novel data demonstrate abnormal systemic and uterine vascular responses during an active CMV infection in both nonpregnant and late pregnant mice. Importantly, despite reduced placental weights, fetal weights were maintained, suggesting effective intrauterine compensation in the mouse model.

Vascular dysfunction in young, mid-aged and aged mice with latent cytomegalovirus infections

“…ϩ was propagated in mouse fibroblasts as previously described (14). An active mCMV infection was detected by staining for ␤-galactosidase protein, expressed from the LacZ insertion.…”

“…Following equilibration, a CCD video camera module (Sony) connected to a compound microscope was used to measure the initial lumen diameter with a video dimension analyzer as previously described (14,20). Vasoconstriction in mesenteric and uterine arteries was assessed following increasing concentrations of the ␣ 1-adrenergic agonist phenylephrine (PE; 10 nM to 10 M; Sigma).…”

“…Vascular resistance and systemic blood pressure are impacted by the mesenteric vasculature. In our previous studies we showed an overall increase in vasodilation in mesenteric arteries isolated from mice actively infected with mCMV (14), which may be to compensate for increased vasoconstrictory activity (6,12,13). It is unknown whether these effects in mesenteric arteries are maintained during mCMV latency and whether the additional stress of aging would reduce the mCMV-mediated increase in vasodilation allowing vasoconstrictory effects to increase vascular tone.…”

“…We hypothesized that the oldest animals infected with CMV at a young age will experience the greatest vascular dysfunction compared with age-matched uninfected controls and all other animal groups. Uterine artery vascular responses are important to reproductive function and we had previously shown decreased vasodilation and increased vasoconstriction in uterine arteries from mCMV-infected pregnant mice (14). Pregnancy and aging are both stress factors for development of vascular dysfunction particularly in the presence of a second stressor such as an infection.…”

“…Previously, we have shown that active mCMV infections impair vascular responses in both mesenteric and uterine arteries isolated from young nonpregnant and late pregnant mice and mounted on a pressure myograph system. These effects likely occur by both direct viral infection of cells within the vascular wall and indirect, systemic effects of the immune system (13,14). What is not yet known is whether vascular changes in these vascular beds are maintained once the active infection becomes latent, particularly during aging.…”