NF2/Merlin in Vascular Smooth Muscle Cells
Abstract
Therapies tailored for persons with neurofibromatosis type 2 (NF2) are limited, and few clinical trials are actively recruiting persons with NF2 for participation. In seeking to identify new therapeutic targets for NF2, we have focused on recent reports demonstrating that hypertension is exceedingly common in persons with NF2 and that some manifestations may be particularly sensitive to therapies that are traditionally used to control blood pressure. In fact, use of a particular blood pressure medication (losartan) was recently shown to enhance radiation therapy in an animal model NF2-associated schwannoma with outcomes that closely mirrored higher-dose radiation. Based on these promising outcomes in animal models and clinical evidence from cohorts of patients with NF2, we have developed animal models carrying mutations in Nf2 in vascular smooth muscle cells alone. These animals develop arterial stiffness and poor blood pressure control that accurately resemble clinical reports from persons with NF2. Both smooth muscle cells and whole arteries from these animals display increased contractility (a feature of hypertension), and we have identified a novel pathway for study that has not previously been explored in the context of NF2. Loss of merlin, the protein encoded by the NF2 gene, in smooth muscle cells results in very low expression of the serotonin transporter. This transporter is primarily responsible for returning serotonin to the intracellular compartment to be degraded, and FDA-approved compounds targeting the serotonin transporter (Selective Serotonin Reuptake Inhibitors or SSRIs) interfere with serotonin metabolism and promote increased binding of serotonin to its receptor. Serotonin helps to control blood pressure but is also a critical mediator of pain signaling pathways. We provide clear evidence that loss of merlin sensitizes smooth muscle cells to angiotensin, a small protein that controls blood pressure and is targeted by losartan. In turn, activation of angiotensin signaling and loss of the serotonin transporter promote the effects of serotonin on the vascular system. The long-term goal of our laboratory is to develop new insights and therapies for NF. Our goal in this Investigator-Initiated Award application is to identify a novel relationship between merlin, angiotensin, and serotonin in the control of blood pressure and arterial stiffness with an eye towards how these mechanisms may be exploited for hypertension and other manifestations related to NF2. At the conclusion of the funding period, we will have (1) defined a clear mechanism linking these important targets to merlin/NF2, (2) developed efficacy data from multiple FDA-approved and experimental therapies that may be used to treat high blood pressure and/or other manifestations of NF2, and (3) generated multiple surveys of small RNA, proteins, and pathways that are dysregulated in merlin-deficient smooth muscle cells, which will significantly inform and impact the NF2 research community.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310240
Entities
People
- Brian K. Stansfield
Organizations
- Augusta University
- United States Army