MMP-15 is upregulated in preeclampsia, but does not cleave endoglin to produce soluble endoglin

PLoS One. 2012;7(6):e39864. doi: 10.1371/journal.pone.0039864. Epub 2012 Jun 29.

Abstract

Preeclampsia is a major pregnancy complication, characterized by severe endothelial dysfunction, hypertension and maternal end-organ damage. Soluble endoglin is an anti-angiogenic protein released from placenta and thought to play a central role in causing the endothelial dysfunction and maternal organ injury seen in severe preeclampsia. We recently reported MMP-14 was the protease producing placentally-derived soluble endoglin by cleaving full-length endoglin present on the syncytiotrophoblast surface. This find identifies a specific drug target for severe preeclampsia; interfering with MMP-14 mediated cleavage of endoglin could decrease soluble endoglin production, ameliorating clinical disease. However, experimental MMP-14 inhibition alone only partially repressed soluble endoglin production, implying other proteases might have a role in producing soluble endoglin. Here we investigated whether MMP-15--phylogenetically the closest MMP relative to MMP-14 with 66% sequence similarity--also cleaves endoglin to produce soluble endoglin. MMP-15 was localized to the syncytiotrophoblast layer of the placenta, the same site where endoglin was localized. Interestingly, it was significantly (p = 0.03) up-regulated in placentas from severe early-onset preeclamptic pregnancies (n = 8) compared to gestationally matched preterm controls (n = 8). However, siRNA knockdown of MMP-15 yielded no significant decrease of soluble endoglin production from either HUVECs or syncytialised BeWo cells in vitro. Importantly, concurrent siRNA knockdown of both MMP-14 and MMP-15 in HUVECS did not yield further decrease in soluble endoglin production compared to MMP-14 siRNA alone. We conclude MMP-15 is up-regulated in preeclampsia, but does not cleave endoglin to produce soluble endoglin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antigens, CD / metabolism*
  • Cohort Studies
  • Endoglin
  • Female
  • Gene Knockdown Techniques
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Matrix Metalloproteinase 15 / deficiency
  • Matrix Metalloproteinase 15 / genetics
  • Matrix Metalloproteinase 15 / metabolism*
  • Pre-Eclampsia / enzymology
  • Pre-Eclampsia / genetics
  • Pre-Eclampsia / pathology
  • Pregnancy
  • Protein Transport
  • Receptors, Cell Surface / metabolism*
  • Solubility
  • Trophoblasts / enzymology
  • Trophoblasts / pathology
  • Up-Regulation*

Substances

  • Antigens, CD
  • ENG protein, human
  • Endoglin
  • MMP15 protein, human
  • Receptors, Cell Surface
  • Matrix Metalloproteinase 15