Cracking the code on APS vasculopathy

Antiphospholipid syndrome is an autoimmune disease that impacts about one in every 2,000 individuals.

APS is best known for increasing your risk of dangerous blood clots, like deep vein thrombosis and stroke. At the same time, a frequently overlooked risk posed by the condition is something called APS vasculopathy.

Impacting 10-20% of patients, APS vasculopathy is defined by the abnormal inward growth of cells within blood vessels.

This thickening of the vessel wall leads to a progressive narrowing of the vessel lumen—the hollow space where the blood is supposed to flow.

This is most likely to occur in the small blood vessels that supply the skin, kidneys, heart, and other organs. The resulting lack of blood flow leads to organ deterioration and eventually failure.

Unfortunately, current treatment options are extremely limited.

A research study led by Jason Knight, M.D., Ph.D., a professor of rheumatology at University of Michigan Health, took a novel approach to uncover new insights into APS.

The work was co-led by Hui Shi, M.D., Ph.D., previously a research fellow at U-M and now an associate professor at Shanghai Jiao Tong University School of Medicine.

The research published in Circulation, the flagship journal of the American Heart Association, started with skin biopsies of patients with severe forms of APS.

The team then used a technique called single-cell sequencing to pinpoint the features of individual blood vessel cells.

When APS blood vessel cells were compared to the cells of individuals without APS, the expression of two proteins particularly stood out, CCN1 and CCN2.

“These cell-communication network proteins are best known for their roles in scarring, also known as fibrosis, but in the context of APS, they appeared to serve a different purpose,” noted Dr. Wenying Liang, one of the lead authors of the study and now an internal medicine resident at McLaren Oakland Hospital.

The abnormally high production of the CCN proteins caused the proliferation of endothelial and smooth muscle cells, both critical building blocks of a blood vessel’s wall. The result was thicker vessel walls, narrower lumens, and—ultimately—less space for the blood to flow.

Of the two CCN proteins, CCN2 appeared to have an especially strong effect on blood vessel cells, raising hope for new treatment strategies.

“Although biologic drugs targeting CCN2 are available, we must now secure buy-in from key stakeholders to bring them into clinical trials for APS,” said Knight.

“In the meantime, we are asking whether there are more easily accessible therapies that may achieve the same biological effects.”

The team members also eventually extended their work beyond the skin and found significant overexpression of CCN1 and CCN2 in the kidneys of APS patients, supporting the idea that skin can provide an accessible window into deeper disease processes in APS.

“The goal of our research has been to develop new treatments for the complications APS causes to vital organs, and we think this timely study brings us one step closer to that,” said Shi. “It is definitely an exciting time for the field.”

“We’ve been working with collaborators around the country to develop a project that will follow at least 100 individuals with APS vasculopathy over an extended period of time,” said Knight.

“In addition to finding new treatment targets, we need to better understand the tempo of clinical changes, so we can develop the rational and efficient clinical trials that our patients deserve.”

Additional authors: Hui Shi, M.D., Ph.D., from the Department of Rheumatology and Immunology, Ruijin Hospital, School of Medicine, Shanghai, Jiao Tong University, Shanghai, China and the Department of Internal Medicine, University of Michigan, Ann Arbor, MI. Wenying Liang, Claire K. Hoy, Cyrus Sarosh, Srilakshmi Yalavarthi, Pooja Kapoor, Lucas Hudgins, Caroline E. Vance, Yu Zuo and Pei-Suen Tsou from the Department of Internal Medicine, University of Michigan, Ann Arbor, MI. Zhixia Yang, Setao Ding, Haoyu Pan and Chengde Yang from the Department of Rheumatology and Immunology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. Qiuyu Wang from the Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China. Yue Shi from the School of Athletic Performance, Shanghai University of Sport, Shanghai, China. Rachel Wasikowski, Lam C. Tsoi, Johann E. Gudjonsson and Allison C. Billi from the Department of Dermatology, University of Michigan, Ann Arbor, MI. Gabriel Figueroa-Parra and Alí Duarte-García from Mayo Clinic, Rochester, MN. Ajay Tambralli and Jacqueline A. Madison from the Department of Internal Medicine, University of Michigan, Ann Arbor, MI and the Department of Pediatrics, University of Michigan, Ann Arbor, MI.

Funding/disclosures: Portions of this work were supported by The Assistant Secretary of Defense for Health Affairs endorsed by the Department of Defense through the Lupus Research Program under Award Number W81XWH-22-1-0895 to Jason Knight, M.D., Ph.D. Opinions, interpretations, conclusions, and recommendations contained herein are those of the author(s) and are not necessarily endorsed by the Department of Defense. PST was partially supported by NIH grant R01AI183620 and the Leo Foundation. JEG and LCT were partially supported by NIH grants P30AR075043 and R01AI130025. Portions of the work were also supported by a grant from the National Natural Science Foundation of China (82271820) and the Innovative Research Team of High-level Local Universities in Shanghai (SHSMU-ZDCX20211002) to HS.

Tech transfer(s)/Conflict(s) of interest: Although not focused on microvascular APS, JSK has done consulting relevant to APS in general for BioCryst, Ouro Medicines, Roche, Roivant Sciences, and Visterra. None of the other authors has any relevant financial conflicts of interest to disclose.

Paper cited: “Microvascular Endothelial Cells License APS Vasculopathy Through YAP1- and CCN2-Mediated Signaling,” Circulation. DOI: 10.1161/CIRCULATIONAHA.125.073552

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