Peripheral Anti-Angiogenic Imbalance during Pregnancy Impairs Myogenic Tone and Increases Cerebral Edema in a Rodent Model of HELLP Syndrome

Abstract

Using an animal model of hemolysis elevated liver enzymes low platelets (HELLP) that has systemic inflammation and neuroinflammation we wanted to determine if blood brain barrier (BBB) permeability, cerebral edema, vascular tone, and occludin expression were altered in pregnant rats. Anti-angiogenic proteins sFlt-1 and sEng (4.7 and 7 µg/kg/day, respectively) were chronically infused into normal pregnant (NP) rats beginning on gestational day 12 via a mini-osmotic pump. On gestational day 19, blood pressure was measured via a carotid catheter and brains were collected. BBB permeability was assessed in select brain regions from rats infused with 0.5 mg/mL Texas Red Dextran and phenylephrine. Occludin, sFlt-1, and sEng were analyzed via western blot or ELISA. Infusion of sFlt-1 and sEng into NP rats increased hemolysis and liver enzymes, and decreased platelets and led to hypertension. HELLP rats had significant impairment in the myogenic response and increased BBB permeability in the posterior cortex and brainstem. Brain water content in the posterior cortex was increased and sEng protein expression in the brainstem was significantly increased in HELLP rats. The results from this study suggest that a peripheral anti-angiogenic imbalance during pregnancy is associated with decreased myogenic tone, vasogenic edema, and an increase in BBB permeability, but not anti-angiogenic imbalance in the brain.

Edema associated with low plasma protein level and any gestational hypertension as warning signs of HELLP syndrome

“…Hecht et al [14] recently identified from 317 autopsies of women who died of eclampsia not only "brain perivascular edema" (68.4%), which was unsurprising, but also liver lesions characterized by "periportal hemorrhage and dilation of the sinusoids" (72.2% in this series) as the predominant problems. The presence of HELLP syndrome is also characterized by impaired capillary perfusion [15] and increased permeability to plasma proteins, and it may be linked to cerebral edema [15][16][17][18].…”

How Soluble Fms-Like Tyrosine Kinase 1 Could Contribute to Blood-Brain Barrier Dysfunction in Preeclampsia?

“…In preeclampsia, the imbalance between angiogenic and anti-angiogenic factors is proposed to play a key role in the increased cerebrovascular permeability ( Bean et al, 2018 ). However, the exact mechanism by which the preeclampsia-mediated alterations in VEGF signaling modify the integrity of the BBB remain poorly known.…”

“…Soluble endoglin (sEng), an anti-angiogenic protein that acts inhibiting the activity of transforming growth factor β1 (TGFβ1) ( Levine et al, 2006 ), is also a contributing mediator. Studies have proposed that high levels are related to the severity of this syndrome as observed in women developing hemolysis elevated liver enzymes low platelets (HELLP) syndrome ( Venkatesha et al, 2006 ), late-onset preeclampsia ( Cim et al, 2017 ), and animal models of HELLP ( Bean et al, 2018 ). TGFβ1 appears to modulate VEGFR2 signaling in endothelial cells, which results on the loss of both tip cell and stalk cell phenotypes ( Jarad et al, 2017 ).…”

“…However, mice overexpressing sFlt-1 and sEng exhibited increased BBB permeability ( Maharaj et al, 2008 ). In a model of HELLP syndrome, induced by chronic administration of sFlt-1 and sEng to pregnant mice, a regional increase in BBB permeability at the posterior cortex was observed ( Bean et al, 2016 , 2018 ). Since the administration of exogenous sFlt-1/sEng leads to the development of a HELLP-like syndrome, other models such as the reduced utero-placental perfusion (RUPP) ( Li et al, 2012 ) could be more suitable to study the cerebrovascular complications of preeclampsia.…”

Pathophysiology of Cerebral Vascular Dysfunction in Pregnancy-Induced Hypertension

“…This soluble receptor sequesters free VEGF, producing an anti-angiogenic imbalance in the maternal circulation during preeclampsia. Bean, et al [ 56 •] utilized a model of sFlt-1 and soluble endoglin (sEng, a soluble receptor for TGF-beta) infusion to interrogate the role of an anti-angiogenic balance in the cerebrovascular manifestations of preeclampsia. They found that this anti-angiogenic balance produced cerebral edema in areas of the brain supplied by the posterior circulation and impaired myogenic tone in the middle cerebral artery.…”