Platelets as therapeutic and diagnostic entity in fibromuscular dysplasia

Project Summary
Fibromuscular Dysplasia (FMD) is a vascular disease predominantly affecting women, characterized by
abnormally shaped blood vessels. While the true incidence of FMD is unknown, although the estimate suggest
it affects around 5% of the population. Accurate diagnosis of FMD remains challenging due to its under
recognition and the lack of a specific blood biomarker. While there is no cure for FMD because the underlying
cause is unknown, stroke is a feared consequence for patients with FMD. Therefore, anti-platelet medications
are given to offset this risk, despite a lack of clinical evidence proving their effectiveness. The abnormal blood
flow (D-Flow) through distorted vessels in FMD patients can lead to biomechanical activation of platelets. In the
absence of vascular tissue availability from these patients, we have used circulating platelets, most abundant
circulating cells to gain insights of this orphan disease. By capitalizing on access to large patient cohort of FMD
patients at the Cleveland Clinic, we have identified a dysregulated platelet activation despite of antiplatelet
therapy, secondary to biomechanical activation in D-flow environments. This project is driven by the working
hypothesis that platelets and platelet-derived extracellular vesicles (PEVs) serve as reservoirs of biomarkers
for diagnosing FMD, predicting stroke risk, and targeting therapeutic interventions. Specific Aim1 will test the
hypothesis that platelet-derived blood biomarkers can be used to diagnose FMD and predict stroke risk with
95% accuracy. Validation in a larger cohort of FMD patients will enable the development of the first blood-
based diagnostic test for FMD patients. Specific Aim 2: We will characterize the platelet phenotype in the
Sm22α-Ubr4KO mouse that mimics FMD in humans. Preliminary data suggest that FMD patients release Platelet
derived extracellular vesicles (PEVs), which behave like "mini platelets" and may contribute to stroke risk, as
evidenced by increased thrombosis in ex vivo experiments. We will also evaluate different anti-platelet therapies
in the Sm22α-Ubr4KO model to identify more effective treatments. Specific Aim 3: We will investigate the
mitochondrial function in FMD patients. Our multi-‘omics analysis has revealed significant mitochondrial
dysfunction in women with FMD. By sequencing the mitochondrial genome, we will identify variants and explore
the potential heritability of the disease. This research will form the foundation of my future studies by linking
platelet mitochondrial dysfunction to thrombosis. By leveraging Cleveland Clinic’s large FMD patient cohort, this
study will provide critical mechanistic insights into FMD and support the development of novel therapeutics to
improve stroke outcomes in this orphan disease.

Grant Number: 1K99HL181079-01
NIH Institute/Center: NIH
Principal Investigator: Anu Aggarwal