Figure 1. Overview of signalling pathways in uterine artery endothelial cell (EC) proliferation during pregnancy.

VEGF, oestrogen and its metabolites via interaction with distinct receptors activate the MAPK pathways, leading to endothelial cell proliferation during pregnancy. VEGF‐A interacts with VEGFR‐2 to activate the Ras–MEK–ERK pathway to promote endothelial cell proliferation (Gualandi L & Claesson‐Welsh L. (2011). Signal transduction by vascular endothelial growth factor receptors. Biochem J 437, 169–183). The findings from the Magness laboratory suggest that this pathway is also utilized by 17‐β‐oestradiol (E2β), norepinephrine (NE), epinephrine (Epi), 2‐hydroxyoestradiol (2‐OHE₂) and 4‐hydroxyoestradiol (4‐OHE₂) in uterine arterial endothelial cells. Exchange protein directly activated by cAMP (EPAC) probably links β2/β3 adrenergic receptors (ARs) to the Ras–MEK–Erk pathway (Borland G, Smith BO & Yarwood SJ. (2009). EPAC proteins transduce diverse cellular actions of cAMP. Br J Pharmacol 158, 70–86.). In addition, E2β, catecholestradiols and catecholamines also stimulate uterine arterial endothelial cell proliferation via activation of p38 mitogen‐activated protein kinase (p38) and c‐Jun N‐terminal kinases (JNK).