Background
Cerebral small vessel disease (SVD) is a very common progressive vascular disease that covers various pathologies all related to the small vessels in the brain. Due to damage or malfunction of these tiny vessels, the cerebral blood-low is reduced leading to chronic damage of tissue over the years.
SVD is a major cause of microinfarcts and microbleeds—types of stroke that often go undetected, but are major contributors to disability and dementia. Despite such a profound impact on brain health, there are no proven treatments for SVD that can prevent, or slow down the progression of this disease. Treatment is currently limited to reducing common vascular risk factors such as hypertension, diabetes mellitus, hyperlipidemia, and smoking. Additional main risk factors are advanced age and genetic factors.
The underlying pathomechanisms of this disease are still not understood. However, hypertension as the leading risk factor and vascular endothelial dysfunction are clearly associated with cSVD. Brain endothelial cells (BECs) have unique roles at the blood-brain barrier (BBB) and in controlling cerebral blood flow (CBF), including sensing moment-to-moment changes in neural activity. We propose this essential integrator function is progressively degraded in SVD and that microvascular BEC dysfunction serves as a nexus for the loss of brain health.
Yet, we have only scratched the surface in understanding the contribution of BECs to vascular control and brain health. Investigators of this network have identified genetic variants in humans that increase the risk for SVD and stroke. In addition, they have developed mice that express such variants in BECs and have shown that they exhibit SVD and brain injury that mimic those in humans. Our preliminary results suggest that, when combined with genetic variants in BECs, hypertension increases SVD and brain injury to a greater extent than either pathology alone.
Objectives
The BRENDA network aims to investigate the BEC-specific mechanisms underlying SVD, ischemic stroke, and intracerebral hemorrhage. Our overarching hypothesis is that BECs have an initiating role in SVD and that genetic predisposition combined with hypertension synergistically drive SVD (two-hit model).
