Is MMP-1 the Culprit Behind Preeclampsia?

January 19, 2011

Preeclampsia is a rapidly progressive condition that affects as many as 8% of all pregnancies. To better understand how and why this process occurs, researchers at Virginia Commonwealth University School of Medicine looked to see if neutrophil infiltration could affect vascular expression of the enzyme matrix metalloproteinase-1 (MMP-1) and other extracellular matrix proteins, which in turn might result in vascular dysfunction in women with preeclampsia.

Preeclampsia is a rapidly progressive condition that affects as many as 8% of all pregnancies. To better understand how and why this process occurs, researchers at Virginia Commonwealth University School of Medicine looked to see if neutrophil infiltration could affect vascular expression of the enzyme matrix metalloproteinase-1 (MMP-1) and other extracellular matrix proteins, which in turn might result in vascular dysfunction in women with preeclampsia.

Professor Guadalupe Estrada-Gutierrez and colleagues examined omental fat biopsy specimens and placentas obtained at the time of cesarean section from healthy pregnant women and women with a diagnosis of preeclampsia. (The researchers chose to study omental specimens because they are representative of systemic blood vessels and contribute to total peripheral vascular resistance.) Preeclampsia was defined as having blood pressure of 140/90 mmHg or higher on two separate readings 6 hours apart as well as proteinuria (0.3 g protein/24 hours or one plus urine dipstick result). Blood samples were obtained during the third trimester to further assist in the study.

The researchers found a significant increase in MMP-1 (7-fold increase) in the blood vessels of women with preeclampsia as compared to pregnant women without preeclampsia; the MMP-1 increases were evident in the endothelium, vascular smooth muscle, and infiltrating leukocytes.

Estrada-Guitierrez and colleagues also found an imbalance in the collagen-regulating genes. Specifically, they noticed that despite the higher levels of MMP-1, mature COL1A1 was not markedly affected, but the precursor form of collagen type I alpha 1 (COL1A1) was absent from blood vessels of women with preeclampsia. This, they surmised, indicated that the synthesis of COL1A1 was reduced.

"Taken together, these data suggest that the increase in MMP-1 could cause vascular dysfunction in preeclamptic women by creating an imbalance between collagen synthesis and collagen breakdown, favoring breakdown," the researchers explained. "These alterations in the vascular collagen type 1 network may be responsible for the edema and protein leakage observed in women with preeclampsia."

PAR-1

The increase of MMP-1s may have additional effects, including the activation of PAR-1; PAR-1 plays critical roles in coagulation, inflammation, and vascular homeostasis. In examining the omental vessels, Estrada-Guitierrez and colleagues found that PAR-1 expression was approximately 9-fold higher in the omental vessels of women with preeclampsia as compared to those who were experiencing a healthy pregnancy. The researchers noted: "Overall, these in vitro and in vivo studies support a model in which infiltrating neutrophils enhance PAR-1 production in vascular smooth muscle, which could be activated by increased levels of MMP-1, providing additional support for the pathogenic role of these inflammatory cells and MMP-1 in preeclampsia."

Vasoconstriction

The researchers also found evidence supporting MMP-1's role in vasoconstriction. Specifically, they found that activated MMP-1 directly caused vessel contraction at 0.25 ng/ml (P < 0.05), 2.5 ng/ml (P < 0.001), and 25 ng/ml (P < 0.001). Since unactivated pro–MMP-1 had no effect on vessel diameter, they concluded that vasoconstriction was due to the enzymatic activity of MMP-1.

Next, they repeated the MMP-1 dose-response test in the presence of a potent and selective non–peptide PAR-1 antagonist and found that vessel contraction was completely abolished. Thus, they concluded, MMP-1's potent vasoconstrictor properties are PAR-1 dependent.

By shedding some light on this common complication and the mechanisms behind it, the researchers have unlocked potential new treatments for women with preeclampsia.

"MMP-1 activation of PAR-1 is a totally new mechanism to explain hypertension," Dr Scott Walsh, professor in the Virginia Commonwealth University School of Medicine's Department of Obstetrics and Gynecology and corresponding author of the report, told the press. "It is possible this could lead to effective treatment of women with preeclampsia by using the PAR-1 inhibitors."

References:

More Information

Preeclampsia Foundation

OBGYN Morning Rounds: Severe Preeclampsia at 28 Weeks

Sources

Estrada-Gutierrez G, Cappello RE, Mishra N, et al. Increased expression of matrix metalloproteinase-1 in systemic vessels of preeclamptic women: A critical mediator of vascular dysfunction. Am J Pathol. 178(1):451-460. http://www.journals.elsevierhealth.com/ periodicals/ajpa/article/PIIS0002944010000490/abstract. Accessed January 19, 2011.

Smith T. VCU research helps explain pregnancy disorder. Richmond Times Dispatch. http://www2.timesdispatch.com/lifestyles/ 2011/jan/06/TDMET01-vcu-research-helps-explain-pregnancy-disor-ar-755837/. Published Jan 6, 2011. Accessed January 19, 2011.

Enzyme may explain preeclampsia symptoms in pregnant women. Sify news. http://www.sify.com/news/enzyme- may-explain-preeclampsia-symptoms-in-pregnant-women-news-international-lbfrugecdgg.html. Published Jan 5, 2011. Accessed January 19, 2011.