Improving Cerebrovascular Function to Increase Neuronal Recovery in Neurodegeneration Associated to Cardiovascular Disease

Abstract

Mounting evidence indicates that the presence of cardiovascular disease (CVD) and risk factors elevates the incidence of cognitive impairment (CI) and dementia. CVD and associated decline in cardiovascular function can impair cerebral blood flow (CBF) regulation, leading to the disruption of oxygen and nutrient supply in the brain where limited intracellular energy storage capacity critically depends on CBF to sustain proper neuronal functioning. During hypertension and acute as well as chronic CVD, cerebral hypoperfusion and impaired cerebrovascular function are often associated with neurodegeneration and can lead to CI and dementia. Currently, all forms of neurodegeneration associated to CVD lack effective treatments, which highlights the need to better understand specific mechanisms linking cerebrovascular dysfunction and CBF deficits to neurodegeneration. In this review, we discuss vascular targets that have already shown attenuation of neurodegeneration or CI associated to hypertension, heart failure (HF) and stroke by improving cerebrovascular function or CBF deficits.

Cerebral Vessels: An Overview of Anatomy, Physiology, and Role in the Drainage of Fluids and Solutes

“…The most important risk factors are advancing age and hypertension, both of which will hamper cerebral blood flow by directly damaging arterial walls and the microvasculature. Patients with SVD and AD often present with increased arterial stiffness, altered BBB permeability, VSMC loss, multiple fenestrations in the internal elastic lamina, remodeled arterial wall basement membranes, pericyte degeneration, increased intercapillary distance, reduced capillary density, increased arteriolar tortuosity, and swelling of astrocyte end feet, ultimately reducing the capacity for an optimal exchange of substances across the capillary endothelium (77)(78)(79)(80). The inefficient transfer of pulsatile energy from the arterial bed toward the capillaries and the venous walls will disrupt hydrostatic forces.…”

Cognitive Impairment in Heart Failure: Landscape, Challenges, and Future Directions

“…Increased level of circulating angiotensin II (Ang-II) during HF process induced perivascular macrophage (PVM) activation, which further regulate vascular permeability and recruit granulocyte. Upon Ang-II binds to angiotensin receptor 1 in the PVMs, the NADPH oxidase 2 is activated to promote ROS overproduction ( 66 , 67 ). ROS, such as superoxide, NO, and ONOO–, increased BBB permeability via activating matrix metalloproteinase, producing oxidative damage to cellular molecules ( 68 ).…”

Cognitive impairment in myocardial infarction and heart failure

“…Upon Ang-II binds to angiotensin receptor 1 in the PVMs, the NADPH oxidase 2 is activated to promote reactive oxygen species (ROS) overproduction. 42,43 ROS such as superoxide, NO, ONOO -, increased BBB permeability via activating matrix metalloproteinase, producing oxidative damage to cellular molecules, suppressing tight junction proteins, and promoting inflammatory cytoskeletal reorganization. 44 The circulating oxidative stress and inflammation could be facilitated to the brain after BBB breakdown to initiate brain oxidative stress, microglial hyperactivation and brain cell death, leading to dendritic spine loss, which is directly response to cognitive impairment.…”

“…The major role of PVMs is to regulate vascular permeability and recruit granulocyte during cerebrovascular injury. Upon Ang‐II binds to angiotensin receptor 1 in the PVMs, the NADPH oxidase 2 is activated to promote reactive oxygen species (ROS) overproduction 42,43 . ROS such as superoxide, NO, ONOO – , increased BBB permeability via activating matrix metalloproteinase, producing oxidative damage to cellular molecules, suppressing tight junction proteins, and promoting inflammatory cytoskeletal reorganization 44 .…”