Cardiovascular adaptations of pregnancy in T and B cell-deficient mice.

The pathophysiology of gestational hypertensive disorders is incompletely defined. T lymphocytes are implicated. Both T and natural killer (NK) cells express RAS and, in implantation sites, NK cells are highly enriched. We hypothesized that T cells and/or NK cells contribute to circulatory control during pregnancy. Using radiotelemetry of arterial pressure, heart rate, and activity, mice without T and B cells (genotypes BALB/c-Rag2(-/-) and NOD.scid) were examined at baseline and across pregnancy. These strains differ in NK cell competency, with Rag2(-/-) being normal and NOD.scid impaired. Circulatory features differed between these inbred strains. Rag2(-/-); had blood pressure responses to pregnancy that did not differ from congenic normal mice. NOD.scid had higher midgestational blood pressure compared with normoglycemic NOD mice (3-5 mm Hg greater than NOD; P < 0.004). In comparison to controls, both T and B strains had much higher heart rates after first trimester that did not remit until parturition (>30 bpm greater than control; P < 0.0001). NOD.scid had additional anomalies, including 90% depletion of circulating NK cells and elevated (57%) proliferation of uterine NK cells within implantation sites. These data demonstrate immune control of midgestational heart rate and suggest NK cells contribute to midpregnancy regulation of mean arterial pressure.

Expression of the vasoactive proteins AT1, AT2, and ANP by pregnancy-induced mouse uterine natural killer cells.

Angiotensin II receptor type 1 (AT1) activation leads to vasoconstriction and type 2 receptor (AT2) leads to vasodilation. Atrial natriuretic peptide (ANP) antagonizes the effects of AT1. In human and murine pregnancies, uterine natural killer (uNK) cells closely associate with decidual blood vessels. Protein localization of AT1, AT2, and ANP to mouse uNK cells was examined between gestation days (gds) 6 and 12, the interval of uNK cell expansion. Percentages of uNK cells expressing AT1 or AT2 changed between gd6 and gd10. Atrial natriuretic peptide did not localize to uNK cells at gd6 or 8, but did colocalize to uNK cells at gd10 and 12, times immediately after spiral arterial modification. This is the first report of AT1, AT2, and ANP expression in uterine immune cells. Expression of these molecules suggests that uNK cells have the potential to contribute to the changes in blood pressure that occur between days 5 and 12 of pregnancy in mice.

Uterine NK cells, spiral artery modification and the regulation of blood pressure during mouse pregnancy.

Reproductive success in mammals involves coordinated changes in the immune and cardiovascular as well as in the neuroendocrine and reproductive systems. This review addresses studies that identify potential links for NK cells and T cells with the local and systemic cardiovascular adaptations of pregnancy. The studies reviewed have utilized immunohistochemisty and in vivo analyses of vascular parameters by ultrasound, chronic monitoring of hemodynamics via radiotelemetric recording and intravital microscopy. At the uterine level, functional subsets of uterine natural killer cells were identified. These included subsets expressing molecules important for vasoregulation, in addition to those previously identified for angiogenesis. Spiral arteries showed conducted responses that could account for conceptus control of vasoactivity and mouse gestational blood pressure 5-phase pattern. Vascular immunology is an emerging transdisciplinary field, critical for both reproductive immunology and cardiovascular disease.