Branching morphogenesis is a key process in the formation of vascular networks. To date, little is known regarding the molecular events regulating this process. We investigated the involvement of synectin in this process. In zebrafish embryos, synectin knockdown resulted in a hypoplastic dorsal aorta and hypobranched, stunted, and thin intersomitic vessels due to impaired migration and proliferation of angioblasts and arterial endothelial cells while not affecting venous development. Synectin(-/-) mice demonstrated decreased body and organ size, reduced numbers of arteries, and an altered pattern of arterial branching in multiple vascular beds while the venous system remained normal. Murine synectin(-/-) primary arterial, but not venous, endothelial cells showed decreased in vitro tube formation, migration, and proliferation and impaired polarization due to abnormal localization of activated Rac1. We conclude that synectin is involved in selective regulation of arterial, but not venous, growth and branching morphogenesis and that Rac1 plays an important role in this process.

Although studies have suggested a role for angiogenesis in determining heart size during conditions demanding enhanced cardiac performance, the role of EC mass in determining the normal organ size is poorly understood. To explore the relationship between cardiac vasculature and normal heart size, we generated a transgenic mouse with a regulatable expression of the secreted angiogenic growth factor PR39 in cardiomyocytes. A significant change in adult mouse EC mass was apparent by 3 weeks following PR39 induction. Heart weight; cardiomyocyte size; vascular density normalization; upregulation of hypertrophy markers including atrial natriuretic factor, β-MHC, and GATA4; and activation of the Akt and MAP kinase pathways were observed at 6 weeks post-induction. Treatment of PR39-induced mice with the eNOS inhibitor l-NAME in the last 3 weeks of a 6-week stimulation period resulted in a significant suppression of heart growth and a reduction in hypertrophic marker expression. Injection of PR39 or another angiogenic growth factor, VEGF-B, into murine hearts during myocardial infarction led to induction of myocardial hypertrophy and restoration of myocardial function. Thus stimulation of vascular growth in normal adult mouse hearts leads to an increase in cardiac mass.

Trivial or mild PPR is a frequent finding on intraoperative TEE. Smaller body size and the use of a bioprosthetic valve are significantly associated with PPR. The clinical significance and natural history of PPR is benign in most cases.

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