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Background: Transforming growth factor beta (TGFβ) blockade via systemic antibody targeting has been shown to augment murine AAA progression in multiple independent studies. Despite these findings, the primary source of protective TGFβ within AAA remains unclear. Previous research conducted in our laboratory demonstrates deletion of platelet-specific TGFβ1 exacerbates aneurysms in the elastase mouse model of AAA. Our present study extends these results by showing a comparable phenotype in the angiotensin II (Ang II) murine model of AAA. Methods and Results: Low density lipoprotein receptor deficient ( Ldlr -/- ) mice with platelet-specific deletion of Tgfβ1 were created by breeding male mice expressing Cre recombinase under the control of a Pf4 promoter to female Tgfβ1 floxed mice (Jackson Labs). Male mice were fed high fat diet 1 week prior to and throughout subcutaneous infusion of AngII (1,000 ng/kg/min). After day 28 of infusion, ex vivo aortic diameter was significantly increased in Cre+ (n = 17) vs Cre- (n = 18) mice ( Cre- : 1.75 ± 0.17 mm; Cre+ : 2.43 ± 0.21 mm; P < 0.05). AAA incidence, defined as aortic diameter ≥ 1.2mm, was 56% for Cre- mice vs. 93% in the Cre+ group. Histological analysis of picrosirius red staining revealed a marked reduction in type 1 abdominal collagen deposition as a proportion of total cellular area in aortas from Cre+ mice versus Cre- controls. OCT embedded sections of aneurysms from both cohorts were also probed for macrophage marker CD68 and analyzed using immunofluorescent microscopy. We found Cre+ aortas had significantly increased macrophage infiltration compared to Cre- aortas. Conclusions: This study of platelet-specific deletion of TGFβ1 in a secondary model of murine AAA supports the conclusion that TGFβ1 sourced form platelets plays a critically important role in the protection of AAA.
Spuzzillo et al. (Wed,) studied this question.