Preeclampsia is a pregnancy-specific hypertensive syndrome that causes substantial maternal and fetal morbidity and mortality. Maternal endothelial dysfunction mediated by excess placenta-derived soluble VEGF receptor 1 (sVEGFR1 or sFlt1) is emerging as a prominent component in disease pathogenesis. We report a novel placenta-derived soluble TGF-beta coreceptor, endoglin (sEng), which is elevated in the sera of preeclamptic individuals, correlates with disease severity and falls after delivery. sEng inhibits formation of capillary tubes in vitro and induces vascular permeability and hypertension in vivo. Its effects in pregnant rats are amplified by coadministration of sFlt1, leading to severe preeclampsia including the HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome and restriction of fetal growth. sEng impairs binding of TGF-beta1 to its receptors and downstream signaling including effects on activation of eNOS and vasodilation, suggesting that sEng leads to dysregulated TGF-beta signaling in the vasculature. Our results suggest that sEng may act in concert with sFlt1 to induce severe preeclampsia.

Abstract-Decreased endothelial NO synthase (eNOS)-derived NO bioavailability and impaired vasomotor control are crucial factors in cardiovascular disease pathogenesis. Hereditary hemorrhagic telangiectasia type 1 (HHT1) is a vascular disorder associated with ENDOGLIN (ENG) haploinsufficiency and characterized by venous dilatations, focal loss of capillaries, and arteriovenous malformations (AVMs). We report that resistance arteries from Eng ϩ/Ϫ mice display an eNOS-dependent enhancement in endothelium-dependent dilatation and impairment in the myogenic response, despite reduced eNOS levels. We have found that eNOS is significantly reduced in endoglin-deficient endothelial cells because of decreased eNOS protein half-life. We demonstrate that endoglin can reside in caveolae and associate with eNOS, suggesting a stabilizing function of endoglin for eNOS. After Ca 2ϩ -induced activation, endoglin-deficient endothelial cells have reduced eNOS/Hsp90 association, produce less NO, and generate more eNOS-derived superoxide (O 2 Ϫ ), indicating that endoglin also facilitates eNOS/Hsp90 interactions and is an important regulator in the coupling of eNOS activity. Treatment with an O 2 Ϫ scavenger reverses the vasomotor abnormalities in Eng ϩ/Ϫ arteries, suggesting that uncoupled eNOS and resulting impaired myogenic response represent early events in HHT1 pathogenesis and that the use of antioxidants may provide a novel therapeutic modality. Key Words: endothelium Ⅲ superoxide Ⅲ vascular disease Ⅲ vascular tone Ⅲ vasodilatation R esistance arteries normally contract in response to increases in perfusion pressure. This reflex, referred to as the myogenic response (MR), plays an important role in the local regulation of vascular tone and blood flow. By limiting the transmission of excessive hemodynamic forces to downstream capillaries and venules, the arterial MR also preserves the structural integrity of the microcirculation. 1 Although the MR is an intrinsic property of vascular smooth muscle, it is modulated by endothelium-derived vasoactive factors, most notably NO. 2 In the vasculature, endothelial NO synthase (eNOS) produces NO in response to humoral and mechanical stimuli via location-specific and dynamic interactions with its various allosteric regulators, including caveolin-1 (Cav-1) and Hsp90. 3-5 Impaired vasomotor control attributable to decreased eNOS-derived NO bioavailability is suggested to be a crucial factor in cardiovascular disease pathogenesis. Moreover, a mathematical model of microcirculatory hemodynamics predicts that a loss of vasomotor control may cause arteriovenous malformations (AVMs). 6 Hereditary hemorrhagic telangiectasia type 1 (HHT1) is a vascular disorder characterized by AVMs. This autosomal dominant disorder is associated with endoglin (ENG) haploinsufficiency 7 and vascular abnormalities ranging from venous dilatations to focal loss of capillaries leading to AVMs. 8 Endoglin (Eng) is a 180-kD glycoprotein expressed on endothelial cells, 9 acting as an ancillary receptor for several transf...