Smooth Delivery: ADAMTS9 Enhances Uterine Smooth Muscle Contractions

04/24/2018

Rates of fetal and maternal morbidity and mortality in the United States are on the rise. A new Cleveland Clinic study shows how abnormal accumulation of extracellular matrix (ECM) prevents smooth muscle cells (SMCs) in the uterus from properly contracting, which can cause prolonged or arrested delivery and lead to poor health outcomes.

ECM is a network of molecules found in the space outside of cells that provides structural support and facilitates communication between cells. Like mortar between bricks, ECM helps hold and anchor nearby cells together.

The vast majority of basic research into the cause of disease focuses on what happens inside cells. In accordance with the emerging principle of dynamic reciprocity—the idea that what happens inside and outside of a cell are connected and can regulate one another—researchers investigated how an extracellular enzyme that breaks down ECM, called ADAMTS9, affects the function of SMCs, which are critical for proper uterine contraction during late stage pregnancy and labor.

The multidisciplinary team of researchers—led by Timothy Mead, PhD, Research Associate, with the support of his mentor, Suneel Apte, MBBS, DPhil, both of the Lerner Research Institute Department of Biomedical Engineering—silenced ADAMTS9 in a preclinical model and cultured human uterine SMCs.

When ADAMTS9 was "turned off" in the preclinical cells, significant delivery complications occurred, which suggests the enzyme is crucial for healthy delivery. The researchers conducted a series of protein and tissue staining analyses in the preclinical and human cells to determine how ADAMTS9 supports this process.

Under normal conditions, ECM is constantly remodeling. It breaks down in the pregnant uterus during late stage pregnancy, allowing SMCs to closely connect with one another and contract to deliver the baby. ADAMTS9, which is normally "turned on" in SMCs, contributes to this process by breaking down the ECM molecule versican.

Dr. Mead and collaborators found that in the absence of ADAMTS9, versican levels were very high. They showed that this over-abundance of versican threw the delicate equilibrium of ECM molecules out of whack—specifically inhibiting SMC differentiation and reducing the number of focal adhesions, which anchor SMCs to ECM and are integral for uterine contraction.

Taken together, these findings suggest that ADAMTS9 contributes to successful SMC connectivity and contraction—and by extension, healthy delivery—by maintaining a proper ECM balance. When ECM accumulates in the uterus, it separates neighboring SMCs and prevents them from optimally communicating with one another and contracting.

Additional studies will be important to elucidate how researchers can target enzymes like ADAMTS9 to ensure they effectively break down versican and other important ECM components in an effort to reduce the rates of delivery-related complications. Drs. Mead and Apte are also interested to study these dynamics in aortic smooth muscle cells to learn if ECM can also be targeted to treat or prevent aortic aneurysm.

This study was published in Cell Reports and supported in part by funds from the National Heart, Lung, and Blood Institute (NIH); the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIH); Sabrina's Foundation and the David and Lindsay Morgenthaler Postdoctoral Fellowship. Dr. Mead is Co-President of the Lerner Research Institute Postdoctoral Association. Dr. Apte is an American Heart Association-Paul G. Allen Frontiers Group Distinguished Investigator.