Mitochondria in cells throughout the body become dysfunctional with age, with the proximate cause of this issue being a decline in the quality control mechanisms responsible for clearing out damaged and worn mitochondria. Researchers here show that the increased levels of reactive oxygen species produced by mitochondria in aged smooth muscle cells is important in the stiffening of blood vessels that occurs with advancing age. This loss of the ability of blood vessels to appropriately constrict and relax in response to circumstances leads to hypertension, a chronic state of raised blood pressure that is very damaging over the long term. In this context, it is worth noting that a clinical trial of a mitochondrially targeted antioxidant showed improvement in smooth muscle function and consequent reduction in blood vessel stiffness.
Aging is characterized by increased aortic stiffness, an early, independent predictor and cause of cardiovascular disease. Oxidative stress from excess reactive oxygen species (ROS) production increases with age. Mitochondria and NADPH oxidases (NOXs) are two major sources of ROS in cardiovascular system. We showed previously that increased mitochondrial ROS levels over a lifetime induce aortic stiffening in a mouse oxidative stress model. Also, NADPH oxidase 4 (NOX4) expression and ROS levels increase with age in aortas, aortic vascular smooth muscle cells (VSMCs), and mitochondria, and are correlated with age-associated aortic stiffness in hypercholesterolemic mice.
The present study investigated whether young mice (4 months-old) with increased mitochondrial NOX4 levels recapitulate vascular aging and age-associated aortic stiffness. We generated transgenic mice with low (Nox4TG605; 2.1-fold higher) and high (Nox4TG618; 4.9-fold higher) mitochondrial NOX4 expression. Young Nox4TG618 mice showed significant increase in aortic stiffness and decrease in phenylephrine-induced aortic contraction, but not Nox4TG605 mice. Increased mitochondrial oxidative stress increased intrinsic VSMC stiffness, induced aortic extracellular matrix remodeling and fibrosis, a leftward shift in stress-strain curves, decreased volume compliance and focal adhesion turnover in Nox4TG618 mice.
Nox4TG618 VSMCs phenocopied other features of vascular aging such as increased DNA damage, increased premature senescence and replicative senescence and apoptosis, increased proinflammatory protein expression and decreased respiration. Aortic stiffening in young Nox4TG618 mice was significantly blunted with mitochondrial-targeted catalase overexpression. This demonstration of the role of mitochondrial oxidative stress in aortic stiffness will galvanize search for new mitochondrial-targeted therapeutics for treatment of age-associated vascular dysfunction.