Importance of Angiogenin and Endothelial Progenitor Cells After Rehabilitation Both in Ischemic Stroke Patients and in a Mouse Model of Cerebral Ischemia

If all this is is a biomarker for predicting recovery then it is completely useless for survivors. 
https://www.frontiersin.org/articles/10.3389/fneur.2018.00508/full?

Marina Gabriel-Salazar¹, Anna Morancho¹, Susana Rodriguez², Xavi Buxó², Nicolás García-Rodríguez², Guillem Colell¹, Albert Fernandez¹, Dolors Giralt¹, Alejandro Bustamante¹, Joan Montaner¹ and Anna Rosell^1*

• ¹Neurovascular Research Laboratory and Neurology Department, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain
• ²Unidad de Rehabilitación Neurológica y Daño Cerebral, Hospital Vall d'Hebron, Barcelona, Spain

Background: Rehabilitation therapy is the only available treatment for stroke survivors presenting neurological deficits; however, the underlying molecules and mechanisms associated with functional/motor improvement during rehabilitation are poorly understood.

Objective: Our aim is to study the modulation of angiogenin and endothelial progenitor cells (EPCs) as repair-associated factors in a cohort of stroke patients and mouse models of rehabilitation after cerebral ischemia.

Methods: The clinical study included 18 ischemic strokes admitted to an intensive rehabilitation therapy (IRT) unit, 18 non-ischemic controls and brain samples from three deceased patients. Angiogenin and EPCs were measured in blood obtained before and up to 6 months after IRT together with an extensive evaluation of the motor/functional status. In parallel, C57BL/6 mice underwent middle cerebral artery occlusion, and the pasta matrix reaching-task or treadmill exercises were used as rehabilitation models. Angiogenin RNA expression was measured after 2 or 12 days of treatment together with cell counts from EPCs cultures.

Results: Brain angiogenin was identified in both human and mouse tissue, whereas serum levels increased after 1 month of IRT in association with motor/functional improvement. EPC populations were increased after stroke and remained elevated during follow-up after IRT. The mouse model of rehabilitation by the task-specific pasta matrix exercise increased the number of EPCs at 2 days and increased angiogenin expression after 12 days of rehabilitation.

Conclusions: Angiogenin and EPCs are modulated by rehabilitation after cerebral ischemia, suggesting that both angiogenin and EPCs could serve as biomarkers of improvement during rehabilitation or future therapeutic targets.

Introduction

Stroke is one of the leading causes of death and long-term disability worldwide and leads to 5 million people becoming permanently disabled annually (1–3). Even with the new advances in diagnosis and therapeutic options that are available in the acute phase of a stroke (4), the only approved treatment in subacute and chronic phases is neurorehabilitation to reduce stroke-related disability, thereby leading to an improved quality of life and independence in daily living activities (5).

Rehabilitation after stroke needs an inter-disciplinary care-team including physiotherapists, occupational therapists, language, and speech therapists, working under the direct supervision of a physiatrist, who might be assisted in medical decisions by the use of biomarkers monitoring the neurorepair process (6). The use of clinical measures, physiological parameters, or neuroimaging biomarkers to predict long-term motor recovery in the context of rehabilitation has been studied in recent years (7, 8), but minor contributions have been achieved for molecular biomarkers. It has been described that the improvements in neurological function during rehabilitation respond to repair or compensatory mechanisms that induce plasticity changes involving multiple molecular pathways (9). By identifying these pathways and bio-molecules, we predict that personalization of rehabilitation treatments may be possible. In this regard, some studies have positively shown associations between the levels of oxidative stress markers, neurotransmitters and proteases in biological fluids, and motor function in stroke patients undergoing rehabilitation programs (10–13).

Angiogenesis and vascular remodeling are mechanisms activated early after stroke which remain elevated from days to several weeks as a response to increased collateral blood supply and tightly coupled to neurogenesis and oligodendrogenesis as part of the endogenous neurorepair response (14–16). Moreover, angiogenesis has been associated with a neurological improvement in animal models of stroke (17–19) and modulated by physical exercise (17, 20). Many angiogenesis-related molecules (both promoters and inhibitors) have been described to participate in angiogenesis in the context of stroke, but less is known about their regulation during rehabilitation. In the present study, we focused on two well-known angiogenesis mediators: a molecular player (angiogenin) and a cellular source which sustains angio-vasculogenesis (endothelial progenitor cells, EPCs); both with unknown role as responders to rehabilitation therapy after stroke. Angiogenin has been widely associated with angiogenesis in cancer disease, participating in cell proliferation, migration, and invasion of endothelial cells (21). Its expression has been identified also in neurons and as part of the secretome of EPCs (22, 23). On the other hand, EPCs are well-known mediators of angio-vasculogenesis and vascular remodeling in the adulthood (24, 25). After stroke, circulating EPCs increase in blood and have been identified as markers of infarct size, neurological status, and functional outcome (26, 27).

Our hypothesis is that angiogenin and EPCs are modulated during rehabilitation after cerebral ischemia serving as biomarkers of functional/motor outcome related to their participation in plasticity mechanisms during neurorepair. To test this hypothesis, our study combines a cohort of stroke subjects under intensive rehabilitation therapy (IRT) in which angiogenin and circulating EPCs levels are analyzed. Additionally, the neurological status is monitored in patients using a battery of tests during a 6-month period. Further, two rehabilitation models in mice after cerebral ischemia (task-specific based exercise or physical exercise) are used, where brain and circulating angiogenin determinations together with EPCs cultures are analyzed.

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