Endothelin and the regulation of peripheral and uteroplacental vascular tone during pregnancy

The mechanism behind the vascular adaptation during pregnancy is poorly understood. The fall in peripheral resistance, particularly in the uterine vasculature, is crucial for sufficient increase in uteroplacental blood flow and thereby for normal fetal growth and development. Pregnancy complications such as preeclampsia or IUGR, are associated with increased vascular resistance and/or compromised uteroplacental blood flow with adverse fetal outcome. The general aim of this thesis was to gain further understanding in the control mechanism of peripheral and uteroplacental vascular tone with special regard to endothelin (ET) - an endothelial-derived peptide with mainly vasoconstrictive properties.

Awake pregnant rats were used to investigate uteroplacental blood flow, measured by microsphere technique, before and after ET-receptor blockade or nitric oxide synthase (NOS) inhibition. ET-receptor blockade was found to increase uteroplacental blood flow significantly, whereas NOS inhibition did not. Further, measurement of ET-receptor protein expression within the uterine vasculature by Western blot, showed a significant increase in the ETBreceptor subtype during pregnancy compared to non-pregnant animals.

In pregnant women the role of endogenous endothelin in the regulation of basal vascular tone and the sensitivity to ET-1 was investigated by forearm plethysmography. The sensitivity to ET-1 was unaltered during normal pregnancy, whereas it was decreased in PE. There was an attenuation of endogenous ET dependent vascular tone during pregnancy. Further, plasma levels of ET-1, the precursor big ET-1, and endothelin converting enzyme (ECE) activity was studied. Plasma ET-1 levels increased in the third trimester and post partum compared to second trimester values in normal pregnancy. Plasma ET-1 levels and ECE-activity were significantly increased in PE compared to normal pregnancy.

The localization of ET-receptors was studied in the human placental bed with immunohistochemistry. Both ETA and ETB receptors are present within the vessel wall of spiral arteries. Considering the limited extent of physiological adaptation of spiral arteries within the placental bed in PE, as confirmed in the present study, the immunoreactivity for ETA-R and ETB-R within the vessel wall was more prominent in PE. Further, the ETB receptor subtype was present in endovascular and interstitial trophoblasts, as well as in decidual cells suggesting a role for ET in the transformation of spiral arteries within the placental bed.

ET receptors are widely distributed within the uteroplacental vasculature in the rat and the human placental bed. This together with the effect on uteroplacental blood flow after ET receptor blockade suggests that the ET system plays a role in the regulation of uteroplacental blood flow. However, its role as a constrictor in the forearm vasculature during pregnancy, in contrast to non-pregnant women, seems less important. This difference may suggests, that an attenuation of endogenous ET dependent vascular tone is one mechanism behind the fall in peripheral vascular resistance during normal pregnancy.

List of scientific papers

I. Ajne G, Wolff K, Fyhrquist F, Carlstrom K, Hemsen-Mortberg A, Nisell H (2003). Endothelin converting enzyme (ECE) activity in normal pregnancy and preeclampsia. Hypertens Pregnancy. 22(3): 215-24.
https://pubmed.ncbi.nlm.nih.gov/14572358

II. Ajne G, Ahlborg G, Wolff K, Nisell H (2004). Contribution of endogenous endothelin-1 to basal vascular tone during normal pregnancy and preeclampsia. Am J Obstet Gynecol.

III. Ajne G, Nisell H, Wolff K, Jansson T (2003). The role of endogenous endothelin in the regulation of uteroplacental and renal blood flow during pregnancy in conscious rats. Placenta. 24(8-9): 813-8.
https://pubmed.ncbi.nlm.nih.gov/13129677

IV. Ajne G, Nisell H, Jansson T (2004). Effects of blockade of the endothelin receptor A and inhibition of nitric oxide synthesis on uteroplacental and renal blood flow in awake pregnant rats. Am J Obstet Gynecol.

V. Ajne G, Papadogiannakis N, Jansson T, Nisell H (2004). Localisation of ETA and ETB receptors in human placental bed and uterine vasculature from pregnant rats. [Manuscript]