SARS-CoV2, Blood Pressure and Natural Killer Cells

The Cardiac Cycle

A beating heart is the first sign of life in the developing fetus. Cells of the heart's ventricular and aortic cavities express various proteins with non-active natriuretic and diuretic peptides in a pattern associated with blood pressure. Activated Corin or Furin proteins cleave these peptides into shorter active forms. The cleavage site often defines how these peptides influence cells and the cellular processes while circulating in blood. But, the heart is not the only place this mix of proteins and peptides are manufactured. From early to late pregnancy Corin level changes were greater in women who developed gestational hypertension, commensurate with diastolic and mean arterial blood pressure and it got doctors and scientists thinking?

NT-proBNP is a pro-hormone, a Corin or Furin dependent peptide from the same molecule as activated BNP. Both are released when pressure changes inside the heart. Circulating levels of NT-proBNP were higher in early and late-onset preeclampsia. BNP mRNA and protein were also detected in placentas from women with preeclampsia and controls. In normal pregnancies, BNP in plasma is stable, but in severe preeclampsia it is elevated. In 181 preeclampsia patients higher levels of Corin were expressed, also secreted from synctiotrophoblasts and extravillous trophoblasts of the placenta.

The secretion of NT-proBNP, and BNP mRNA and receptors were investigated in cultured primary trophoblasts. Low levels of NT-proBNP were found in the supernatants of term, but not first-trimester trophoblasts. In preeclampsia patients Corin mRNA and protein in uterine tissue were significantly lower, but plasma Corin higher, compared to normal pregnancies. These apparently conflicting reports may relate to local blood pressure.

A paper studying Atrial Natriuretic Peptide (ANP) identified that Corin and ANP promoted trophoblast invasion and spiral artery remodeling in the developing placenta. Pregnant Corin or ANP-deficient mice developed high blood pressure and proteinuria, characteristics of preeclampsia. Further, trophoblast invasion and uterine spiral artery remodeling were markedly impaired. Consistently ANP potently stimulated human trophoblasts invading in Matrigels. That Corin is up-regulated with stromal cell decidualization and strongly localized provides compelling evidence to support localized, but not circulating Corin activating ANP within these uterine cells. This may then invite trophoblast and Natural Killer (NK) cell invasion and the ultimate handshake of fetal trophoblasts with maternal endothelial cells lining spiral arteries of the developing placenta.

In early pregnancy NK cells expand to become the largest population of immune cells in decidua lining the uterus (uNK). They are closely associated with the development of blood vessels including spiral artery remodeling and possess a functional Renin- Angiotensin system, cornerstones of blood pressure. ANP antagonizes Angiotensin II receptor type 1 (AT1) leading to vasoconstriction. The ratio of uNK cells expressing AT1 markedly changed between gestation day 6 and 10. At day 10-12 ANP strongly co-localized to uNK cells at implantation sites, immediately after spiral arterial modification. Expression of vasoregulatory molecules by uNK cells suggests they contribute to the changes in blood pressure that occur between days 5 and 12 coincidental with their expansion during normal pregnancy in mice.

Studies of patients with Pulmonary Arterial Hypertension have also implicated BNP in the decline of NK cells and CD8+ T-Cells. A similar depletion was recently reported in Coronavirus  patients and expression of NT-proBNP was significantly elevated.  It is reasonable to infer that blood pressure and NK cells are associated especially in the tight confines of pulmonary capillaries or placental tissue.  Perhaps its their capacity to express molecules that participate in Corin activated vasoregulation through natriuretic peptides and to be immunoreactive, or perhaps their reaction to kill infected cells results from it - who knows?

In addition to the well documented natriuresis, diuresis and vasodilation, BNP may also modulate immune and inflammatory reaction to cardiac injury. BNP depletes monocytes, B lymphocytes and NK cells in peripheral blood. BNP regulates the chemotaxis of monocytes and production of inflammatory molecules by macrophages. BNP may promote cardiac neutrophil infiltration and also have direct effects on matrix remodeling and wound healing. All of these characteristics have been observed in lungs of critical care and deceased Coronavirus patients.