Biomedical subjects

Demetra Perlegas

Publications and source records attributed to Demetra Perlegas.

3 recordsLinked to original sources

PubMed2004

ANG II type 2 receptor regulates smooth muscle growth and force generation in late fetal mouse development.

Although evidence from culture studies implicates the angiotensin II (ANG II) type 2 receptor (AT(2)R) in the regulation of growth and differentiation of arterial smooth muscle (SM) cells (SMC), the lack of its expression in adult arteries has precluded direct investigation of its role in vivo. The goal of the present study was to determine the role of AT(2)R in the control of fetal SMC growth, contractility, and differentiation during vascular development. Determination of isometric tension in fetal aortas showed potentiated ANG II-induced contraction by treatment with the selective AT(2)R antagonist PD-123319, demonstrating the presence of functional AT(2)Rs that mediate reduced force development in vascular SMC. In direct contrast to numerous cell culture studies, proliferation indexes were decreased rather than increased in aortic SMC of fetal homozygous AT(2)R knockout compared with wild-type or heterozygous knockout mice. Experiments using SMC tissues from heterozygous female AT(2)R knockout mice, which are naturally occurring chimeras for AT(2)R expression, showed that AT(2)R mRNA expression was exactly 50% of that of wild type. This indicated that loss of AT(2)R expression did not confer a selective advantage or disadvantage for SMC lineage determination and expansion. Real time RT-PCR analyses showed no significant difference in expression of SM-alpha-actin, SM myosin heavy chain, and myocardin in various SM tissues from all three genotypes, suggesting that knockout of AT(2)R had no effect on subsequent SMC differentiation. Taken together, results indicate that functional AT(2)R are expressed in fetal aorta and mediate reduced force development but do not significantly contribute to regulation of SMC differentiation.

Actins↗

PubMed2004

Phosphorylation regulates Id3 function in vascular smooth muscle cells.

Understanding the mechanisms that regulate cell cycle progression in vascular smooth muscle cells (VSMCs) is key to understanding and modulating vascular lesion formation. Results of the present study provide the first evidence that phosphorylation of the helix-loop-helix factor Id3 in VSMCs occurs in vitro and in vivo and provides a regulatory switch controlling Id3-induced regulation of p21Cip1 and VSMC growth.

Angiotensin II↗

PubMed2004

Intron retention generates a novel Id3 isoform that inhibits vascular lesion formation.

The expression of intron-containing messages has been shown to occur in a variety of diseases including lactic acidosis, Cowden Syndrome, and several cancers. However, it is unknown whether these intron-containing messages result in protein production in vivo. Indeed, intron-containing RNAs are typically retained in the nucleus, targeted for degradation, or are repressed translationally. Here, we show that during vascular lesion formation in rats, an alternative isoform of the helix-loop-helix transcription factor Id3 (Id3a) generated by intron retention is abundantly expressed. We demonstrate that Id3 is expressed early in lesion formation when the proliferative index of the neointima is highest and that Id3 promotes smooth muscle cell (SMC) proliferation and S-phase entry and inhibits transcription of the cell-cycle inhibitor p21(Cip1). Using an Id3a-specific antibody developed by our laboratory, we show that Id3a protein is induced during vascular lesion formation and that Id3a expression peaks late when the proliferative index is low or declining and extensive apoptosis is observed. Furthermore, Id3a fails to promote SMC growth and S-phase entry or to inhibit p21(Cip1) promoter transactivation. In contrast, Id3a stimulates SMC apoptosis and inhibits endogenous Id3 production. Adenoviral delivery of Id3a inhibited lesion formation in balloon-injured rat carotid arteries in vivo. These data describe a novel feedback loop whereby intron retention generates an Id3 isoform that acts to limit SMC growth during vascular lesion formation, providing the first evidence that regulated intron retention can modulate a pathologic process in vivo.

Adenoviridae↗