Upregulation of VEGF and PEDF in Placentas of Women with Lower Extremity Venous Insufficiency during Pregnancy and Its Implication in Villous Calcification

Abstract

Pregnancy is a period in a woman's life in which changes can occur that affect different physiological processes. Common conditions during this period include vascular changes, such as lower extremity venous insufficiency (VI). This is an observational, analytical, and prospective cohort study in which 114 pregnant women were analyzed, of which 62 were clinically diagnosed with VI. In parallel, 52 control patients without VI (HC) were studied. The aim of this study was to observe changes in angiogenesis and inflammation markers as well as the presence of calcium deposits. The expression of vascular endothelial growth factor (VEGF), transforming growth factor-β (TGF-β), and pigment epithelium-derived factor (PEDF) was analyzed by immunohistochemistry and RT-qPCR. The presence of calcium deposits was revealed using the von Kossa method. In the placentas of mothers with VI, gene expression of VEGF (34.575 [32.380–36.720] VI vs 32.965 [30.580–36.320] HC) and PEDF (25.417 [24.459–27.675] VI vs 24.400 [23.102–30.223] HC) significantly increased, as was protein expression in the placental villi. An increase in calcium deposits was observed in the placentas of women with VI (72.58% VI/53.84% HC). This study revealed the existence of cellular damage in the placental villi of mothers with VI with tissue implications such as increased calcification.

Lipidomic profiling of chorionic villi in the placentas of women with chronic venous disease

“…Several pathogenic mechanisms that affect the placenta in this disease have been described such as cell hypoxia, oxidative stress, extracellular matrix remodeling, and angiogenesis/lymphogenesis [12]. While CVD is a less serious condition, in prior work we also detected these changes in the placentas of women with venous insufficiency, indicating the possible impact of venous disease in these patients with CVD [9,[13][14][15]. Chronic venous insufficiency has also been associated with a series of changes in cell signaling and in the behavior of smooth muscle cells.…”

Increased Angiogenesis and Lymphangiogenesis in the Placental Villi of Women with Chronic Venous Disease during Pregnancy

“…Pregnancy causes haemodynamic and mechanical changes, triggering vascular complications such as lower extremity CVD [23]. Our previous studies showed how impaired venous hypertension and venous return resulting from CVD during pregnancy created an environment of cellular hypoxia with associated cell damage, producing extracellular matrix remodelling [10][11][12]. In the present study, we saw an increase in the proangiogenic and lymphangiogenic markers CD31, D2-40, Flt-1, and PIGF in placental villi of women with CVD during pregnancy.…”

“…We also saw this abnormal profile of Flt-1 and PIGF in placental villi, both of which were upregulated in the extracellular matrix. Placental villi of women with CVD have shown an increased expression of VEGF [12], explaining how vascular compromise resulting from CVD during pregnancy induces angiogenesis and lymphangiogenesis in placental villi. The placentas of our women with CVD had more villi with PAS-positive material than the control placentas.…”

“…The roles of all these changes in the placenta have not yet been fully elucidated. We have previously shown that lower extremity CVD during pregnancy is associated with some placental changes, such as extracellular matrix remodelling or increased placental apoptosis and villous calcification, along with increased expression of tissue hypoxia markers [10][11][12]. These mechanisms are also dysregulated at the placental level in other important vascular diseases, such as preeclampsia and intrauterine foetal growth restriction [13][14][15].…”

“…Placental growth factor (PIGF) has an important role in angiogenesis, as well as in the proper function of the placenta [16,17]. In women with CVD during pregnancy, overexpression of vascular endothelial growth factor (VEGF) has been reported, explaining its role in the disease's pathogenesis [12]. Likewise, the VEGF receptors VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-2) play roles in various vascular diseases, such as preeclampsia [18,19].…”