Genetic deletion of the DNA damage repair protein, ATM kinase, is not sufficient to induce vascular dysfunction in young mice

Abstract

Ataxia telangiectasia mutated (ATM) kinase orchestrates the cellular response to double stranded DNA breaks, phosphorylating and activating downstream targets that lead to cell cycle arrest or apoptosis, as well as by recruiting the machinery necessary for DNA repair. In the vasculature, ATM may play a critical role in maintaining genomic stability, thereby preserving vascular function, as aberrant DNA repair has been implicated in vascular dysfunction. Here, we evaluated several measures of vascular function in ATM knockout (ATM −/−) and wildtype (ATM +/+) mice (4–6 mo, n=7–9/group). Aortic pulse wave velocity, a measure of large artery stiffness, was similar between groups (P>0.05). Furthermore, using an automated capture and analysis system we assessed markers of microvascular perfusion and glycocalyx properties. Perfused microvascular density, a measure of the number of perfused microvessels in a given area, and red blood cell (RBC) fraction, a marker of the heterogeneity of RBCs between microvessel segments, were not significantly different between groups (P>0.05). Likewise, perfused boundary region, a measure of endothelial glycocalyx barrier function, was not significantly different between ATM −/− and ATM +/+ controls (P>0.05). Furthermore, we examined endothelium‐dependent dilation and nitric oxide (NO) bioavailability in mesenteric arteries by measuring vasodilation to acetylcholine (ACh) in the absence and presence of the nitric oxide synthase inhibitor, L‐NAME. Maximal vasodilation to ACh did not differ between groups (P>0.05). Likewise, the contribution of NO to maximal vasodilation was similar between ATM −/− and ATM +/+ mice (P>0.05). Next, we assessed smooth muscle responsiveness to NO by measuring vasodilation to the NO donor, sodium nitroprusside (SNP). Maximal vasodilation to SNP did not differ between groups (P>0.05). Lastly, we evaluated the passive mechanical properties of isolated mesenteric arteries and found no differences in vessel lumen diameter in response to increasing pressure between ATM −/− and ATM +/+ mice (P>0.05). In conclusion, these findings suggest that removal of a major kinase involved with double stranded DNA damage signaling does not affect vascular function in young mice. This could be due to several reasons. First, young mice may have not accumulated sufficient DNA damage and mutagenesis to induce dysfunction or second, signaling downstream from DNA damage may drive vascular dysfunction. Thus, future studies are warranted that examine the role of ATM kinase in vascular function in response to conditions that augment DNA damage.Support or Funding InformationFunding Information: Funded in part by awards from the NIH, R01 AG048366, R01 AG050238, K02 AG045339 and K99 AT010017, and by US Department of Veterans Affairs 1I01BX002151.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.