Immunometabolism, vascular function and atherosclerosis

Cardiovascular disease (CVD) is among the leading causes of death worldwide and atherosclerosis is the primary underlying cause. Several studies in humans have shown that elevated blood leukocytes increase CVD risk. Pathways that regulate cholesterol accumulation in hematopoietic stem cells (HSCs) or macrophages, or hyperglycemia, affect the production of leukocytes, and may thus affect atherogenesis. We found that disturbances in intracellular cholesterol trafficking in Niemann-Pick type C1 (NPC1) disease, an inborn error of metabolism, promote HSCs mobilization to the spleen, likely contributing to splenomegaly, an early symptom of NPC1 disease. We showed that fasting-induced hypoglycemia in a mouse model for glycogen storage disease type Ia (GSD Ia), also an inborn error of metabolism, decreases pro-inflammatory Ly6Chi monocytes upon fasting and proposed that this may explain the limited atherogenesis in GSD Ia patients. We also investigated whether cholesterol accumulation in smooth muscle cells (SMCs) affected vascular function and atherogenesis. SMCs are located in the media of arteries and regulate vasoconstriction via α1-adrenergic receptor (α1-AR) signaling. We found that SMC cholesterol accumulation increased α1-AR dependent vasoconstriction in mice in vivo. While we did not find effects on atherosclerosis, we found that SMC cholesterol accumulation increases bladder size dramatically, in part due to increased SMC constriction. We propose that SMC cholesterol accumulation mechanistically links hypercholesterolemia and bladder outlet obstruction in humans