TABLE 3.

Description and summary of the cardiovascular phenotypes observed in MDM2 transgenic mouse model.

Transgenic mice model	Type of genetic modification	Site of transgenic modification	Cardiac or vascular phenotype
MDM2-null	MDM2 null mice. MDM2 mutant lacking exon 10–12 or 7–12 were.	Whole body	Embryonic lethality occurs before cardiac development (Jones et al., 1995; Montes de Oca Luna et al., 1995)
MDM2 transgenic mice	Full length MDM2 overexpression under the control of its native promoter region. fourfold increase in MDM2 mRNA expression. MDM2 transgenic mice were generated in both p53 wild-type and p53-null backgrounds	Whole body	Independent of p53 background, mice with MDM2 transgene have a higher proportion of hemangiosarcoma than p53-null mice with normal levels of MDM2 (Jones et al., 1998).
Hypomorphic MDM2 mice	Downregulation of protein expression by 70% using a hypomorphic allele MDM2puro and a recombined null allele MDM2Δ 7–9 (Mendrysa et al., 2003)	Whole body	Capillary rarefaction and lack of angiogenesis in response to physiological stimulus in the skeletal muscle (Roudier et al., 2012)
			Enhanced cardiac/cardiomyocyte hypertrophy, and increased alteration of myocardial tissue and function after ischemia (Toth et al., 2006)
Endothelial MDM2-KO mice	Tie2-Cre driven knock-down of MDM2 in endothelial cell lineage	Endothelial lineage cells	Embryonic lethality at E10.5 due to vascular remodeling defect, i.e., enlargement of the aortic lumen, the cardinal veins and the extraembryonic vasculature (Zhang et al., 2014).
Cardiomyocyte MDM2-KO mice	αMyHC-Cre transgene was used to induce MDM2 deletion in cardiomyocytes	Cardiomyocytes	Embryonic lethality at E9.5 failure to develop a functional heart (Grier et al., 2006)
Inducible Endothelial MDM2-KO mice i-EC-MDM2KO	Cross breeding of Pdgfb-Cre-ER mice with mice harboring the floxed MDM2 alleles	Induction of endothelial-specific MDM2 deletion by tamoxifen	Abnormal swelling of animals 5 days after the injection of tamoxifen Death of all i-EC-MDM2-KO mice 16 days after tamoxifen injection (Yokoyama et al., 2019)
Inducible Cardiomyocyte specific MDM2-KO mice	Cardiac muscle a-myosin heavy chain 6 promoter drives the expression of Cre under the control of Tamoxifen Tg(Myh6-Cre/Esr1)	Induction of cardiomyocytes deletion by hydroxytamoxifen.	Cardiomyocytes-specific deletion of MDM2 lead to spontaneous concentric hypertrophy and cardiac dysfunction and early mortality (Hauck et al., 2017).
Inducible smooth muscle specific MDM2-KO mice i-SMC-MDM2-KO mice	Cross breeding of SMC-specific SM22 promoter (SM-CreERT2) mice with mice harboring the floxed MDM2 alleles	Induction of smooth muscle cell-specific MDM2 deletion by tamoxifen	Cre activity was not found in the cardiovascular system nor in the aorta. Death of all i-SMC-MDM2-KO mice 12 day post tamoxifen injection due to gastrointestinal alterations (Boesten et al., 2006).