Essential role for thymosin ß4 in regulating vascular smooth muscle cell development and vessel wall stability.

RATIONALE: Compromised development of blood vessel walls leads to vascular instability that may predispose to aneurysm with risk of rupture and lethal hemorrhage. There is currently a lack of insight into developmental insults that may define the molecular and cellular characteristics of initiating and perpetrating factors in adult aneurismal disease. OBJECTIVE: To investigate a role for the actin-binding protein thymosin ß4 (Tß4), previously shown to be proangiogenic, in mural cell development and vascular wall stability. METHODS AND RESULTS: Phenotypic analyses of both global and endothelial-specific loss-of-function Tß4 mouse models revealed a proportion of Tß4-null embryos with vascular hemorrhage coincident with a reduction in smooth muscle cell coverage of their developing vessels. Mechanistic studies revealed that extracellular Tß4 can stimulate differentiation of mesodermal progenitor cells to a mature mural cell phenotype through activation of the transforming growth factor-beta (TGFß) pathway and that reduced TGFß signaling correlates with the severity of hemorrhagic phenotype in Tß4-null vasculature. CONCLUSIONS: Tß4 is a novel endothelial secreted trophic factor that functions synergistically with TGFß to regulate mural cell development and vascular wall stability. These findings have important implications for understanding congenital anomalies that may be causative for adult-onset vascular instability.

Feasibility of comparing medical management and surgery (with neurosurgery or stereotactic radiosurgery) with medical management alone in people with symptomatic brain cavernoma - protocol for the Cavernomas: A Randomised Effectiveness (CARE) pilot trial.

INTRODUCTION: The top research priority for cavernoma, identified by a James Lind Alliance Priority setting partnership was 'Does treatment (with neurosurgery or stereotactic radiosurgery) or no treatment improve outcome for people diagnosed with a cavernoma?' This pilot randomised controlled trial (RCT) aims to determine the feasibility of answering this question in a main phase RCT. METHODS AND ANALYSIS: We will perform a pilot phase, parallel group, pragmatic RCT involving approximately 60 children or adults with mental capacity, resident in the UK or Ireland, with an unresected symptomatic brain cavernoma. Participants will be randomised by web-based randomisation 1:1 to treatment with medical management and with surgery (neurosurgery or stereotactic radiosurgery) versus medical management alone, stratified by prerandomisation preference for type of surgery. In addition to 13 feasibility outcomes, the primary clinical outcome is symptomatic intracranial haemorrhage or new persistent/progressive focal neurological deficit measured at 6 monthly intervals. An integrated QuinteT Recruitment Intervention (QRI) evaluates screening logs, audio recordings of recruitment discussions, and interviews with recruiters and patients/parents/carers to identify and address barriers to participation. A Patient Advisory Group has codesigned the study and will oversee its progress. ETHICS AND DISSEMINATION: This study was approved by the Yorkshire and The Humber-Leeds East Research Ethics Committee (21/YH/0046). We will submit manuscripts to peer-reviewed journals, describing the findings of the QRI and the Cavernomas: A Randomised Evaluation (CARE) pilot trial. We will present at national specialty meetings. We will disseminate a plain English summary of the findings of the CARE pilot trial to participants and public audiences with input from, and acknowledgement of, the Patient Advisory Group. TRIAL REGISTRATION NUMBER: ISRCTN41647111.

Intracranial Masson Lesion Following Stereotactic Radiosurgery for Treatment of Intracranial Arteriovenous Malformations.

OBJECTIVES: Masson tumor or intravascular papillary endothelial cell proliferation was first described in 1923. Only a few cases of intracranial Masson tumor have been reported following stereotactic radiosurgery (SRS). We report a series of 6 cases, age range 28-56 years, with intracranial Masson tumor following SRS for treatment of an intracranial arteriovenous malformation (AVM). METHODS: We performed a retrospective case note review, reviewed the imaging, SRS records, and neuropathology specimens following surgical excision. RESULTS: In our series all patients received Leksell SRS with the periphery of the AVM receiving doses ranging from 22-25 Gy. The time lapse from SRS to a clear enhancing mass appearing on imaging ranged from 5-10 years. Four patients underwent craniotomy and excision of the enhancing lesion for persistent edema and an enlarging cyst resulting in a resolution of symptoms. CONCLUSIONS: SRS is an effective treatment for obliteration of intracranial AVMs.

Thymosin beta4 facilitates epicardial neovascularization of the injured adult heart.

Ischemic heart disease complicated by coronary artery occlusion causes myocardial infarction (MI), which is the major cause of morbidity and mortality in humans (http://www.who.int/cardiovascular_diseases/resources/atlas/en/index.html). After MI the human heart has an impaired capacity to regenerate and, despite the high prevalence of cardiovascular disease worldwide, there is currently only limited insight into how to stimulate repair of the injured adult heart from its component parts. Efficient cardiac regeneration requires the replacement of lost cardiomyocytes, formation of new coronary blood vessels, and appropriate modulation of inflammation to prevent maladaptive remodeling, fibrosis/scarring, and consequent cardiac dysfunction. Here we show that thymosin beta4 (Tbeta4) promotes new vasculature in both the intact and injured mammalian heart. We demonstrate that limited EPDC-derived endothelial-restricted neovascularization constitutes suboptimal "endogenous repair," following injury, which is significantly augmented by Tbeta4 to increase and stabilize the vascular plexus via collateral vessel growth. As such, we identify Tbeta4 as a facilitator of cardiac neovascularization and highlight adult EPDCs as resident progenitors which, when instructed by Tbeta4, have the capacity to sustain the myocardium after ischemic damage.

Thymosin beta4 and Ac-SDKP: tools to mend a broken heart.

Thymosin beta4 - an endogenously occurring 43 amino acid peptide - has recently been shown to possess cardioprotective properties in the setting of acute myocardial infarction. This review focuses on the reported mechanisms of action through which Thymosin beta4 might accomplish this effect and the clinical prospects for its use as a therapeutic agent.

Thymosin beta4 and angiogenesis: modes of action and therapeutic potential.

Here we review the mechanisms by which Thymosin beta4 (Tbeta4) regulates angiogenesis, its role in processes, such as wound healing and tumour progression and we discuss in more detail the role of Tbeta4 in the cardiovascular system and significant recent findings implicating Tbeta4 as a potential therapeutic agent for ischaemic heart disease.