The Serine Protease HtrA1 Is Upregulated in the Human Placenta during Pregnancy

Abstract

(AB) S U M M A R Y The placenta has a dynamic and continuous capacity for self-renewal. The molecular mechanisms responsible for controlling trophoblast proliferation are still unclear. It is generally accepted that the simultaneous activity of proteins involved in cell proliferation, apoptosis, and extracellular matrix degradation plays an important role in correct placental development. We investigated in depth the expression of the serine protease HtrA1 during pregnancy in human placenta by in situ hybridization and immunohistochemistry, we demonstrated that HtrA1 displayed a low level of expression in the first trimester of gestation and a strong increase of HtrA1 expression in the third trimester. Finally, by electron microscopy, we demonstrated that HtrA1 was localized either in the cytoplasm of placental cells, especially close to microvilli that characterized the plasma membrane of syncytiotrophoblast cells, or in the extracytoplasmic space of the stroma of placental villi, particularly in the spaces between collagen fibers and on collagen fibers themselves. The expression pattern of HtrA1 in human placentas strongly suggests a role for this protein in placental development and function. Moreover, on the basis of its subcellular distribution it can be postulated that HtrA1 acts on different targets, such as intracellular growth factors or extracellular matrix proteins, to favor the correct formation/function of the placenta.

Distinct expression and localization of serine protease HtrA1 in human endometrium and first‐trimester placenta

“…A previous study reported the expression of HtrA1 during placental development in the human, but it focused on the transition from the first to the third trimester of pregnancy (De Luca et al, 2004). In the present study, we investigated the expression of HtrA1 mRNA and determined the cellular localization of HtrA1 protein during early placental development in the human.…”

HtrA1-dependent proteolysis of TGF-β controls both neuronal maturation and developmental survival

“…Ubiquitously expressed in normal human adult tissues, 13 HtrA1 contains in addition to a highly conserved protease domain (trypsin like serine protease domain), an insulin growth factor-binding domain, a kazal type S protease inhibitor domain followed by one or two post-synaptic disclarge zona domains and a follistatin-like domain. 10 There is increasing evidences that HtrA1 regulates several physiological and pathological processes including tumour development, 14 Alzheimer's disease (AD), 15 placentation, 16 age-related macular degeneration 17 and osteoarthritis. 10 However, the mechanism(s) by which it regulates these processes has(ve) not been fully elucidated.…”

“…10 However, the mechanism(s) by which it regulates these processes has(ve) not been fully elucidated. Considering its subcellular distribution, either found as a secreted protein or in the cytoplasm of the cells, 16 HtrA1 could act on different targets including extra-cellular matrix proteins. Interestingly, both HtrA1 and HtrA3 isoforms have been reported to inhibit TGF-b signalling during development 18,19 through a proteolyticallydependent interaction with ligands of the TGF-b family.…”

HTRA1 (HtrA serine peptidase 1)

“…Upregulation of HTRA1 was observed in endometrial glands and decidual cells during preparation of endometrium for embryo implantation and during the first trimester of placentation (Nie et al, 2006). However, the highest expression of HTRA1 was detected in placenta in the third trimester of gestation (De Luca et al, 2004). These data suggest an important role of HtrA1 in placenta development and function.…”