Abstract Body: Background
The maternal heart adapts to extreme hemodynamic shifts in pregnancy by undergoing physiologic hypertrophy. Canonical Insulin-like Growth Factor-1 (IGF1) signaling is thought to dictate exercise-induced physiologic cardiac hypertrophy, but it is unclear whether this also applies in pregnancy.
Methods
Homozygous female mice possessing loxP sites flanking exon 3 of the Igf1r gene (B6;129-Igf1r^tm2Arge/J Jax Strain #012251) were injected with a cardiac-targeted AAV9 containing Cre recombinase under control of the troponin promoter at 8 weeks of age. Following knockout of Igf1r in cardiomyocytes, these females were mated and sacrificed at postpartum day 21. Serial M-mode echocardiography was performed on cardiac IGF1 Receptor knockout (cIGF1RKO) mice and Igf1r floxed mice not given cre (Cre Negative) at 3 timepoints post-Cre-injection: 1) pre-pregnancy, 2) late pregnancy (E18.5), and 3) postpartum day 21. Upon sacrifice at postpartum day 21, gross heart size was measured and compared to body weight, tibia length, and kidney and liver weights. These same methods were performed on age-matched nonpregnant cIGF1RKO and Cre negative mice for comparison.
Results
Both cIGF1RKO and Cre negative mice tolerated pregnancy and birth, producing adequately sized litters (5+ pups). Despite the lack of Igf1r, the hearts of cIGF1RKO mice could still grow during pregnancy, with a weight increase of 30mg (p = 0.0065, cIGFRKO nonpregnant vs PPD21 heart weight). Similarly, Cre negative mice hearts were 40mg larger at PPD21 compared to nonpregnant controls (p = 0.0012). Serial echocardiography and left ventricular mass estimates mirrored gross heart weights seen on sacrifice.
These preliminary findings distinguish pregnancy-induced physiologic cardiac hypertrophy from exercise, suggesting IGF1 is not a dominant player in maternal cardiac reprogramming. To account for potential compensation of IGF1 signaling through the cardiac insulin receptor (cIR), ongoing studies include verifying these findings in cIGF1RKO mice with a heterozygous deletion of cIR. Future work will interrogate which signaling pathways are indeed essential for pregnancy-induced cardiac growth and aim to identify potential therapeutic targets relating to maternal cardiovascular health.