Lipoprotein lipase activation is a novel vascular anti-contractile mechanism that is lost in aging

Abstract

Increasing incidence of cardiovascular events with age can be attributed to the natural deterioration in organ function, and manifests through a range of vascular phenotypes that include, endothelial dysfunction, hypercontractility, stiffening and remodeling, inflammation, and oxidative stress. Given the aging global population, the identification and translation of novel mechanisms and therapeutics will be essential to increase longevity and prevent premature death and disability. Physiologically, perivascular adipose tissue (PVAT) is known to impact vasculature by exerting an anti-contractile effect mediated by the biosynthesis and liberation of a myriad of anti-contractile molecules (e.g., adipokines). However, this anti-contractile function declines with age and in related diseases. Therefore, our study aimed to restore the anti-contractile effect of PVAT in arteries from aged animals. Specifically, we predicted that increasing lipoprotein lipase (LPL) activity would reinstate the anti-contractile effect of PVAT on aged arteries. To assess this hypothesis, mesenteric resistance arteries (MRA), with (+) and without (-) PVAT, were isolated from male Fisher 344 rats aged 3 (3M) or 16 months (16M) and mounted on a wire myograph. Phenylephrine (PE) concentration-response curves were measured in the presence or absence of LPL activator, NO-1886 (Ibrolipim, 10uM). As expected, PVAT exerted significant anti-contractile effect in MRA, regardless of age [PE 100uM (%), 3M (-PVAT): 112.4±13.3 vs. 3M (+PVAT): 27.6±28.5 {Figure 1.a.} and 16M (-PVAT): 115.4±23.1 vs. 16M (+PVAT): 35.0±34.1 {Figure 1.b.}]. Contrary to our hypothesis, NO-1886 had no effect on the anti-contractile effect of PVAT in 3M or 16M rats [PE 100uM (%), 3M (+PVAT +vehicle): 30.0±34.3 vs. 3M (+PVAT +NO-1886): 47.9±29.8 {Figure 1.c.} and 16M (+PVAT +vehicle): 48.6±42.3 vs. 16M (+PVAT +NO-1886): 60.0±36.9 {Figure 1.d.}]. Surprisingly, we observed an effect of NO-1886 in MRA in the absence of PVAT. Specifically, NO-1886 significantly decreased phenylephrine-induced contraction in 3M rats, but not 16M rats [PE 100uM (%), 3M (-PVAT +vehicle): 112.4±13.3 vs. 3M (-PVAT +NO-1886): 37.8±22.2 {Figure 1.e.} and 16M (-PVAT +vehicle): 115.4±23.1 vs. 16M (-PVAT +NO-1886): 103.1±23.1 {Figure 1.f.}]. Overall, this suggests that LPL has an important physiological role in controlling vascular contraction and this novel anti-contractile mechanism of LPL diminishes with biological age. Funding: NHLBI (R00HL151889), NIGMS (1P20GM103641 - Pilot Project), NIA (K01AG061263), UofSC SOM (Startup funds) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.