The influence of barosensory vessel mechanics on the vascular sympathetic baroreflex: insights into aging and blood pressure homeostasis

We assessed the influence of barosensory vessel mechanics (magnitude and rate of unloading and time spent unloaded) as a surrogate for baroreceptor unloading. In young men, aortic unloading mechanics are important in regulating the operating point of the vascular sympathetic baroreflex, whereas in middle-aged men, these arterial mechanics do not influence this operating point. The age-related increase in resting muscle sympathetic nerve activity does not appear to be driven by altered baroreceptor input from stiffer barosensory vessels.

Premature arterial stiffening in Hutchinson-Gilford Progeria Syndrome linked to early induction of Lysyl Oxidase (LOX) and corrected by LOX inhibition

SUMMARYArterial stiffening is a hallmark of premature aging in Hutchinson-Gilford Progeria Syndrome (HGPS), but the key molecular regulators initiating arterial stiffening in HGPS remain unknown. To identify these early events, we compared arterial mechanics and ECM remodeling in very young HGPS (LMNAG609G/G609G) mice to those of age-matched and much older wild-type (WT) mice. Biaxial inflation-extension tests of carotid arteries of 2-month mice showed that circumferential stiffness of HGPS arteries was comparable to that of 24-month WT controls whereas axial arterial stiffening, an additional hallmark of normal aging, was mostly spared in HGPS. In an effort to identify underlying mechanisms, we examined expression levels of the major stiffness-regulatory molecules in WT and HGPS arteries. Transmission electron microscopy revealed slightly increased amounts of collagen within the elastin folds of HGPS carotid arteries, but this change was barely detectable by immunostaining carotid cross sections or qPCR of isolated aortas for collagens I, III, or V. Elastin integrity was also similar in the WT and HGPS arteries. In contrast, immunostaining readily revealed an increased expression of Lysyl oxidase (LOX) protein in young HGPS carotid arteries relative to aged-matched WT controls. Further analysis showed that HGPS arteries express increased amounts of LOX mRNA, and this effect extends to each of the arterial LOX family members. Remarkably, treatment of HGPS mice with the pan-LOX inhibitor β-aminopropionitrile (BAPN) restored near-normal circumferential arterial mechanics to HGPS carotid arteries, mechanistically and causally linking LOX upregulation to premature arterial stiffening in HGPS. Finally, we show that this premature increase in arterial LOX expression in HGPS foreshadows the increased expression of LOX that accompanies circumferential arterial stiffening during normal aging.