Preeclampsia and intrauterine growth restriction (IUGR) are pregnancy-specific disorders that share a common pathophysiology. Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor that plays an important role in placental development. HIF-1α is elevated in preeclamptic placentas and induces soluble vascular endothelial growth factor receptor-1 (sFLT-1), a central factor in preeclampsia and IUGR pathogenesis. Our objective was to investigate the effects of HIF-1α overexpression on pregnancy in mice. C57BL/6J pregnant mice were systemically administered either adenovirus expressing stabilized HIF-1α (cytomegalovirus [CMV]-HIF), luciferase control (CMV-Luc), or saline on gestational day 8. Pregnant mice overexpressing HIF-1α had significantly elevated blood pressure and proteinuria compared with pregnant controls. HIF-1α mice showed fetal IUGR, decreased placental weights, and histopathological placental abnormalities compared with control mice. Glomerular endotheliosis, the hallmark lesion of preeclampsia, was demonstrated in the kidneys of these mice relative to the normal histology in control mice. Moreover, liver enzyme levels were significantly elevated, whereas complete blood counts revealed significant anemia and thrombocytopenia in CMV-HIF mice compared with controls. Blood smears confirmed microangiopathic hemolytic anemia in CMV-HIF mice, consistent with HELLP (hemolysis, elevated liver enzymes, and low platelets)-like syndrome. CMV-HIF mice showed elevation in serum sFLT-1 and soluble endoglin, providing a mechanistic explanation for the observations. Collectively, our results suggest a possible role for HIF-1α in the pathogenesis of both preeclampsia and IUGR.

The objective of this work was to determine markers of endothelial cell activation in valves from patients with antiphospholipid syndrome (APS) and heart valve involvement, in order to establish a role for endothelial cells in the pathogenesis of the valvular disease. Sixteen valves from ten patients with APS, obtained from autopsies or removed during valve replacement, were studied. Two groups of valves were used as controls. One group included seven normal valves from patients who died from non-cardiac diseases. The other group of valves were obtained from patients with bacterial endocarditis during autopsies or valve replacement operations. Immunoperoxidase and immunofluorescence stainings with antibodies to human immunoglobulins, endothelial cells, alpha3beta1 integrin, collagen IV, laminin and fibronectin were employed. Three histopathological patterns were apparent: normal valves, valves with verrucous endocarditis and valves with fibrocalcific changes. In all the valves with verrucous endocarditis the following findings were observed: (1) increased expression of the alpha3beta1 integrin on the endothelial cells, (2) increased amount of collagen IV, laminin and fibronectin, (3) proliferation of blood vessels and (4) linear subendothelial deposition of immunoglobulins and complement. The valves with fibrocalcific changes were deformed and showed a thick layer of collagen IV, laminin and fibronectin, yet in two valves the indothelial cells showed an expression of the alpha3beta1 integrin. The control valves did not express the integrin and had only a thin subendothelial band of collagen IV. In valves from patients with APS, 1 markers of endothelial cell activation are upregulated while the inflammatory exudate is scant. There is also a prominent deposition of immunoglobulins in the valves from patients with APS, suggesting a possible association between the deposition of the antibodies and the activation of the endothelial cells in APS.

No abstract