The multi-functional peptide adrenomedullin (
Adm
= gene, AM = protein) plays important roles in embryonic development and disease. Previous studies demonstrated that
Adm
knockout mice die at embryonic day 13.5 with small, disorganized hearts and hypoplastic lymphatic vessels, highlighting the importance of this peptide in normal cardiovascular development. Since
Adm
knockout animals are embryonic lethal, our goal was to generate and characterize a novel model of
Adm
over-expression to study the role of
Adm
during development and disease processes. Through gene targeting techniques, we generated a novel mouse model of
Adm
over-expression, abbreviated as
Adm
hi/hi
. When we assessed gene expression of
Adm
from 10 different tissues, we found
Adm
hi/hi
mice express 3- to 15-fold more
Adm
than wildtype littermates. Additionally, peptide levels of AM in lung and kidney, as well as circulating plasma levels of AM were elevated 3-fold over wildtype mice, indicating a functional increase in AM. Our initial analysis revealed that adult
Adm
hi/hi
mice have larger heart weight to body weight ratios than wildtype littermates (4.93±0.23 vs. 5.96±0.29, n = 11-12). We found that compared to wildtype,
Adm
hi/hi
embryos have more proliferating cells during heart development (14.46±1.11 vs. 31.97±2.84, n=4), indicating that hyperplasia drives
Adm
hi/hi
heart enlargement. By crossing the
Adm
hi/hi
line to different tissue-specific Cre lines, we were able to excise the stabilizing bovine growth hormone 3’UTR, thereby returning
Adm
expression levels back to wildtype in cells with active Cre recombinase. Using this approach, we identified the epicardium as a major source of AM during cardiac development. In conclusion, we found that AM derived primarily from the epicardium drives cardiac hyperplasia during embryonic development resulting in persistent, enlarged hearts of adult
Adm
hi/hi
mice. Since our
Adm
hi/hi
mice recapitulate the 3-fold plasma elevation of AM observed during human disease, this mouse line will be a useful tool for studying the role of elevated AM during disease.
The Role of CLEC-2 and Its Ligands in Thromboinflammation