Matrix Metalloproteinase Enhances Big-Endothelin-1 Constriction in Mesenteric Vessels of Pregnant Rats With Reduced Uterine Blood Flow

Abstract

Abstract-Preeclampsia is a leading cause of maternal and fetal morbidity/mortality; however, the pathophysiological mechanisms are unclear. Vascular endothelial dysfunction in preeclampsia has been partially attributed to changes in endothelin-1 (ET-1). Several enzymes, including matrix metalloproteinases (MMPs; particularly MMP-2), cleave the inactive precursor big ET-1 (bET-1) to active ET-1. Notably, expression levels of MMP-2 have been shown to be on the increase in women who subsequently develop preeclampsia. We hypothesized that the increased MMP-2 expression leads to increased bET-1 conversion, thereby increasing vasoconstriction in preeclampsia. A reduced uteroplacental perfusion pressure (RUPP) model of preeclampsia in the rat was used to assess mesenteric artery vascular function. Responses to bET-1 (3-310 nmol/L) and ET-1 (1-200 nmol/L) were studied in the presence or absence of inhibitors of enzymes known to cleave bET-1. Vascular contractility in response to bET-1 was greater in RUPP than Sham (P<0.001), whereas neither responses to ET-1 nor maximal contractility to high potassium salt solution (123.70 mmol/L) were different. MMP inhibition with GM6001 (30 μmol/L) significantly decreased responses to bET-1 in RUPP (P<0.001) but not Sham-operated rats. Interestingly, combined treatment with GM6001 and L-NG-nitroarginine methyl ester (100 μmol/L) revealed a NO modulation of MMPs that was reduced in RUPP. In summary, we found increased vascular contractility to bET-1 in the RUPP model of preeclampsia that was likely attributable to upstream enzymatic pathways. These data are consistent with a greater contribution of MMP to cleavage of bET-1 to ET-1 ex vivo in RUPP, suggesting that this enzyme may be partially responsible for increased bET-1-induced contractility.

The Endothelin System: A Critical Player in the Pathophysiology of Preeclampsia

“…Interestingly, the expression levels of MMPs (particularly MMP-2 and MMP-1) have been shown to increase in women who subsequently develop PE. Abdalvand et al recently hypothesized that the increased MMP-2 expression leads to increased big-ET-1 conversion, and therefore increasing vasoconstriction [45]. They reported increased vascular contractility to big-ET-1 in the reduced uterine perfusion pressure (RUPP) model of PE that was likely attributable to upstream enzymatic pathways.…”

Maternal Vascular Physiology in Preeclampsia

“…63 Others have shown that contractile responses to inactive precursor big ET-1 were increased in mesenteric arteries from this experimental model and that inhibition of matrix metalloproteinase, an enzyme that catalyzes the conversion of big ET-1 to ET-1, abolished the enhanced contractile responses. 65 Collectively, studies on endothelium-derived constrictors suggest that TxA 2 and ET-1 contribute to maternal vascular dysfunction in women with preeclampsia and in animal models with experimental preeclampsia. Neither the human nor the animal investigations, however, provide any insight into whether changes in TxA 2 and ET-1 production and actions contribute to the pathogenesis of preeclampsia or are consequences of the syndrome.…”

Downregulation of Microvascular Endothelial Type B Endothelin Receptor Is a Central Vascular Mechanism in Hypertensive Pregnancy

“…ET A R is mainly expressed in vascular smooth muscle (VSM) to induce vasoconstriction, whereas ET B R is predominately expressed in endothelial cells to induce the release of vasodilator substances, 14,15 and also plays a role in ET-1 clearance. 16 Although a role of ET-1 and its vasoconstrictor ET A R in modulation of cardiovascular-renal function during HTN-Preg has been suggested, 3,17-19 the role of vasodilator endothelial ET B R during Norm-Preg and HTN-Preg, and the post-ET B R mediators involved are less clear.…”