Neural metabolic imbalance induced by MOF dysfunction triggers pericyte activation and breakdown of vasculature

Vascular Homeostasis and Inflammation in Health and Disease—Lessons from Single Cell Technologies

“…In addition to the two main vascular cell types, numerous brain cells including astrocytes and microglia have close contacts with the blood vessels and are able to directly modulate their activity ( Figure 1 D). Consistent with this, changes in the neural metabolic environment [ 34 ], neural activity [ 92 ], inflammatory signals [ 93 ], buildup of toxic products such as β-amyloid [ 94 ], and infection [ 95 ], can all modulate vascular properties such as blood flow and permeability.…”

“…The vascular system not only supplies our bodies with nutrients and oxygen, but is also directly involved in the execution of immune reactions to pro-inflammatory stimuli. There are a multitude of stimuli that lead to vascular inflammation including alterations in blood flow and shear stress, increased concentration of low-density lipoproteins (LDLs), metabolic changes such as increased fatty acids, hypertension, agiotensin II signaling, as well as pro-inflammatory cytokines and chemokines that are upregulated in response to viral or bacterial infections [11,[32][33][34]. Vascular inflammation is accompanied by active attraction of circulating leukocytes to the site of injury and their transmigration into the intima of the vessel wall, to clear the tissue from the source of inflammation and dead cells and ultimately resolve the inflammation.…”

“…Although there is now increasing appreciation that vascular defects are key parts of the pathology of neurodegenerative disorders, whether environmental factors could also contribute to neurovascular defects remains unclear. Recent work has suggested that a defective metabolic environment could induce vascular inflammation and increased vascular permeability in the developing brain [34]. Through scRNA-seq and transcriptomic analyses of FACS-isolated neural and vascular cells, it was established that increased free fatty acids can trigger a toll-like receptor 4 (TLR4)-NFkB-dependent pro-inflammatory response in brain pericytes.…”

“…Through scRNA-seq and transcriptomic analyses of FACS-isolated neural and vascular cells, it was established that increased free fatty acids can trigger a toll-like receptor 4 (TLR4)-NFkB-dependent pro-inflammatory response in brain pericytes. This ultimately results in morphological changes in brain pericytes, associated with vascular dilation, breakdown of the extracellular matrix and increased vascular permeability [34]. This finding is compelling, as metabolic changes are thought to be a core component of neurodegenerative and neurodevelopmental disorders [110,111] and APOE, a key genetic risk factor for AD, plays a central role in lipid metabolism and transport [112,113].…”

Beyond barrier functions: Roles of pericytes in homeostasis and regulation of neuroinflammation

“…This resulted in white matter dysfunction and led to neurodegeneration and cognitive decline. A recent study has also shown that that defective lysine acetylation, owing to lack of an acetyl transferase, in neural cells significantly increased the accumulation of long chain fatty acids (LCFAs) in parenchyma (Sheikh et al, 2020). LCFAs were shown to induce the TLR4-NFκB-dependent inflammatory response in pericytes that led to vascular dysfunctions such as hemorrhages.…”