Mice homozygous for the SM22&alpha;-mTFPI transgene are viable and fertile, with the mouse SM22&alpha; promoter fragment directing expression of a mouse tissue factor pathway inhibitor cDNA sequence encoding the TFPI&alpha; isoform (TFPI&alpha; is the predominant TFPI protein isoform in humans).

As such, SM22&alpha;-mTFPI transgenic mice have vascular smooth muscle cell-directed overexpression of TFPI in a tissue-specific and local manner. Specifically, homozygous SM22&alpha;-mTFPI transgenic mice from founder line 1661 have transgene mRNA levels approximately 4-fold higher than endogenous TFPI mRNA in aortic homogenates. Similarly, TFPI activity of carotid artery homogenates from homozygous transgenic mice showed 2- to 3-fold increase compared to wildtype mice. SM22&alpha;-mTFPI mice have increased circulating levels of TFPI antigen, but no increase in TFPI activity in plasma, compared to wildtype mice.  Transgenic TFPI expression is also observed in smooth muscle-rich tissues such as lung, heart and kidney.  Local TFPI overexpression does not affect hemostasis, but significantly attenuates ferric chloride-induced arterial thrombosis.

<p>When SM22&alpha;-TFPI transgenic mice are made deficient of endogenous TFPI expression (by breeding with <i>Tfpi</i>-knockout mice), the resulting double mutant homozygous mice demonstrate that transgenic SM22&alpha;-directed TFPI overexpression is not sufficient to rescue TFPI-null embryonic lethality.

<p>Additionally, SM22&alpha;-TFPI mice fed a high-fat diet demonstrate lower cholesterol levels than wildtype mice. Similarly, when SM22&alpha;-TFPI transgenic mice are made deficient of endogenous apolipoprotein E (by breeding with apoE-knockout mice) for high-fat diet studies, SM22&alpha;-directed TFPI overexpression attenuates aortic plaque burden and results in lower plasma cholesterol levels compared to apoE-/- mice.

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These SM22&alpha;-mTFPI transgenic mice have vascular smooth muscle cell-directed overexpression of a mouse tissue factor pathway inhibitor cDNA sequence encoding the TFPI&alpha; isoform (TFPI&alpha; is the predominant TFPI protein isoform in humans). These mice may be useful in studying the role of vascular TFPI expression in intravascular thrombosis, the tissue factor pathway in vascular disease, coagulation, innate immunity, angiogenesis, and lipid metabolism.

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