Decreased expression of caveolin-1 have relevance to promoted senescence in preeclamptic placenta

Aging refers to a decline in cells, tissues, and organs function over time, resulting in the weakened adaptability of the body to stress, with progressive vulnerability to numerous disease (1, 2). Senescence at the cellular level is induced by shortening of the telomere due to repeated cell division, DNA damage, and abnormal activation of oncogenes (3, 4). In aging cells, irreversible cell cycle arrest occurs via the p53 and pRb pathways, sustained by p16INK4a and p21WAF/CIP1 (5, 6). These cells are metabolically activated; however, their growth is inhibited, and they secret a substance called senescence-associated secretory phenotype (SASP), used as a biomarker of cellular senescence (7, 8).

Caveolin-1 (CAV-1), encoded by CAV-1 gene, exists in plasma membranes of most cells as a structural protein that form caveolae (9). CAV-1 proteins are composed of four domains, of which the caveolin scaffolding domain (CSD) directly interacts with multiple signaling molecules (10). Through these domains, CAV-1 functions as a transport vesicle; however, it is also significant in signal transduction, cellular metabolism, cholesterol homeostasis, endocytosis, tumor promotion and suppression (11-13). These roles of CAV-1 induce significant changes in various cells. CAV-1 is overexpressed in malignant cells, senescent human diploid fibroblasts (HDFs), mesenchymal stem cells, and bone marrow (14, 15). Moreover, CAV-1 deficiency induced early cellular senescence in fat atrophy, pathological hypertrophy of the heart, and insulin resistance (16, 17). In addition, it has a notable role as a regulator of cell cycle proliferation in a p53/p21 dependent manner (18).

p53, a tumor suppressor protein, is also involved in cell aging through cell cycle arrest, DNA repair, and apoptosis (19, 20). The activation of p53 by various stimuli initiates senescence-associated pathways, shortens lifespan and accelerates aging (21). p21, the cyclin-dependent kinase inhibitor 1, is a cell cycle inhibitor that acts as a target of p53 activity and is among the initial downstream targets of p53 identified as a mediator of p53-dependent cell cycle arrest (22, 23). p21 is expressed through a p53-independent pathway occasionally during normal tissue development or cell differentiation (24).

Cellular senescence occurs physiologically during cell-to-cell fusion in the placenta during pregnancy. Cytotrophoblasts (CTs) differentiate into syncytiotrophoblast (STBs) through such process. STBs promote a stable implantation process through interaction with decidual cells and plays a crucial role in placental development by modifying the vascular structure of spiral artery in the early pregnancy. This process is maintained for 12 weeks to term as part of the physiologic aging of placental cells (25, 26). Failure of this process is associated with complications such as fetal growth restriction (FGR), fetal death, preterm labor, and preeclampsia (PE) in the second trimester (27, 28). A factor accelerating these changes is increased oxidative stress under perfusion into the intervillous space, pathologically promoting placental senescence. These phenomena lead to the accumulation of SASP, structural changes, destruction of decidual cells, and promotion of apoptosis in related cells. CAV-1 contributing to premature cellular senescence suggests that similarly changes would be observed in PE–complicated placenta.

Therefore, this study aimed to examine the association between altered CAV-1 expression and cellular senescence and its effects on PE’s pathogenesis and onset time in an animal model of PE and in the placentas and sera of pregnant women complicated with PE.

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