Platelet TGF-β1 contributions to plasma TGF-β1, cardiac fibrosis, and systolic dysfunction in a mouse model of pressure overload

Abstract

Circulating platelets contain high concentrations of TGF-␤1 in their ␣-granules and release it on platelet adhesion/activation. We hypothesized that uncontrolled in vitro release of platelet TGF-␤1 may confound measurement of plasma TGF-␤1 in mice and that in vivo release and activation may contribute to cardiac pathology in response to constriction of the transverse aorta, which produces both high shear and cardiac pressure overload. Plasma TGF-␤1 levels in blood collected from C57Bl/6 mice by the standard retrobulbar technique were much higher than those obtained when prostaglandin E 1 was added to inhibit release or when blood was collected percutaneously from the left ventricle under ultrasound guidance. Even with optimal blood drawing, plasma TGF-␤1 was lower in mice rendered profoundly thrombocytopenic or mice with selectively low levels of platelet TGF-␤1 because of megakaryocytespecific disruption of their TGF-␤1 gene (Tgfb1 flox ). Tgfb1 flox mice were also partially protected from developing cardiac hypertrophy, fibrosis, and systolic dysfunction in response to transverse aortic constriction. These studies demonstrate that plasma TGF-␤1 levels can be assessed accurately, but it requires special precautions; that platelet TGF-␤1 contributes to plasma levels of TGF-␤1; and that platelet TGF-␤1 contributes to the pathologic cardiac changes that occur in response to aortic constriction. (Blood.

Transforming Growth Factor-β and Inflammation in Vascular (Type IV) Ehlers–Danlos Syndrome

“…Ongoing microvascular damage, even in younger patients without complications, may lead to increased platelet turnover, degranulation, and subsequent TGF-β1 release into circulation as recently described in a mouse model of cardiac pressure overload. 35 Interestingly, we found that CRP was not significantly elevated in MFS, suggesting a different biomarker profile from VEDS.…”

The role of transforming growth factor (TGF)-β in the infarcted myocardium

“…The contributions of other cell types have not been convincingly documented. Platelets have been suggested to be an important source of TGF-β1 in the pressureoverloaded myocardium (29); however, their role as a source of growth factors in the infarcted myocardium has not been systematically investigated. Lymphocyte subsets and mast cells infiltrate the infarcted heart (30)(31)(32)(33) and are capable of producing TGF-βs.…”

Identification of the Thiol Isomerase-binding Peptide, Mastoparan, as a Novel Inhibitor of Shear-induced Transforming Growth Factor β1 (TGF-β1) Activation

“…Platelets contain 40-to 100-fold more TGF-␤1 than other cell types (2,3), perhaps reflecting a role in wound healing after hemostasis is achieved. The pathological importance of platelet TGF-␤1 has been highlighted by the recent discovery that platelet TGF-␤1 can confer metastatic potential on tumor cells in synergy with NFB signaling (4), and our recent report that targeted deletion of platelet and megakaryocyte TGF-␤1 can protect mice from developing cardiac hypertrophy, fibrosis, and systolic dysfunction in response to constriction of the transverse aorta (5).…”