Healthy cerebral vasculature and adequate blood flow determine overall brain health. Vascular cognitive impairment and dementia (VCID) has now been recognized as a clinical condition with cerebrovascular dysfunction as the underlying pathological mechanism. Aging and diabetes are independent risk factors for vascular disease, and the prevalence of diabetes is higher among older adults and is expected to rise. Accumulated evidence suggests that bone marrow-derived hematopoietic stem/progenitor cells (HSPCs) maintain vascular health and promote re-endothelialization and revascularization following vascular damage. This innate vascular protection is diminished with aging and diabetes due to impaired mobilization of HSPCs from bone marrow into circulation and decreased ability to repair damaged blood vessels. Therefore approaches that preserve HSPC mobilization and function will prevent the development of VCID in older adults with diabetes. We hypothesize that the vasoprotective axis of renin angiotensin system, confers mobilization and reparative functions in HSPCs, and that early interventions that activate this pathway would preserve innate vasoprotection and prevents the development of vascular disease with aging and diabetes. This hypothesis is based on our novel findings that showed angiotensin converting enzyme-2 that generates heptapeptide angiotensin (Ang)-(1-7), the endogenous activator of Mas receptor (MasR), is down-regulated with aging and diabetes in CD34+ HSPCs. Importantly, genetic deficiency of MasR (MasR-KO) precipitated HSPC mobilopathy and vasoreparative dysfunction following ischemic vascular injury, similar to aging and diabetes. Pharmacological treatment with Ang-(1-7) reversed HSPC mobilopathy and restored ischemic vascular repair in diabetic mice. The long-term goal of this proposal is to provide proof-of-concept for the potential of ACE2 or MasR activation or cell-based therapies that involve overexpression of ACE2 or Ang-(1-7) in the treatment of VCID. The investigator has expertise in all of the technologies needed to accomplish the objective except experimental evaluation of cognitive functions in aging mice with diabetes. The first step towards meeting with the objective is to acquire and install the necessary equipment for cognitive evaluation in mice, Morris water maze and polyvalent system for fear-conditioning response. Secondly, we wish to evaluate the beneficial effect of Ang-(1-7) on the cognitive decline in older mice with diabetes, and will carry out in vitro studies to determine the reactivity and mitochondrial function in brain arterioles. Thirdly, we wish to determine HSPC and vascular dysfunctions in a mouse model of Alzheimer?s dementia. Overall, this study will provide a novel mechanism-based approach for the reversal as well as prevention of vascular cognitive impairment in older adults with diabetes. We hope that the ?administrative supplement-research? would help us venture into the hypothesis-driven research program with the goal of providing novel mechanism-based approaches for the treatment of vascular cognitive disorders.
Healthy cerebral vasculature and adequate blood flow determine overall brain health. Vascular cognitive impairment and dementia (VCID) has now been recognized as a clinical condition with cerebrovascular dysfunction as the underlying pathological mechanism. Aging and diabetes are independent risk factors for vascular disease, and the prevalence of diabetes is higher among older adults and is expected to rise. Bone marrow-derived hematopoietic stem/progenitor cells (HSPCs) have the property of regenerating damaged blood vessels and this protective function is decreased with aging and diabetes due to the dysfunction of HSPCs. In this proposal, we ought to test the beneficial effects of an endogenous pathway, which is known to be vasoprotective, ACE2/Angiotensin-(1-7)/MasR pathway. This hypothesis is based on our novel findings that showed angiotensin converting enzyme-2 that generates heptapeptide angiotensin (Ang)-(1-7), the endogenous activator of Mas receptor (MasR), is down-regulated with aging and diabetes in CD34+ HSPCs. Importantly, genetic deficiency of MasR (MasR-KO) precipitated HSPC mobilopathy and vasoreparative dysfunction following ischemic vascular injury, similar to aging and diabetes. Pharmacological treatment with Ang-(1-7) reversed HSPC mobilopathy and restored ischemic vascular repair in diabetic mice. The long-term goal of this proposal is to provide proof-of-concept for the potential of ACE2 or MasR activation or cell-based therapies that involve overexpression of ACE2 or Ang-(1-7) in the treatment of VCID. To accomplish this, we wish to acquire the necessary equipment for cognitive evaluation in mice, Morris water maze and polyvalent system for fear- conditioning response. We will evaluate the beneficial effect of Ang-(1-7) on the cognitive decline in older mice with diabetes, and will carry out in vitro studies to determine the reactivity and mitochondrial function in brain arterioles. Finally, we will determine HSPC and vascular dysfunctions in a mouse model of Alzheimer?s dementia. Overall, this study will provide a novel mechanism-based approach for the reversal as well as prevention of vascular cognitive impairment in older adults with diabetes. We hope that the ?administrative supplement-research? would help us accomplish our long-term goal.
