Biomedical subjects

Lawrence D Adams

Publications and source records attributed to Lawrence D Adams.

5 recordsLinked to original sources

PubMed2005

Expression profiling identifies smooth muscle cell diversity within human intima and plaque fibrous cap: loss of RGS5 distinguishes the cap.

BACKGROUND: The fibrous cap of the atherosclerotic lesion is believed to be critical to stability because disruption of the cap is the final event leading to plaque rupture. We have, therefore, used expression arrays to define the phenotype of the cap and other plaque components. METHODS AND RESULTS: To identify unique expression programs able to distinguish the smooth muscle of the cap from other plaque smooth muscle cells, RNA profiles were determined in human carotid artery media, nonatherosclerotic adjacent intima, fibrous cap of advanced atherosclerotic plaques, and whole advanced plaque with cDNA arrays covering 21,000 or 26,000 Unigene clusters. The molecular signature of each tissue was dominated by a core gene-set with differential expression of <1% of clusters assayed. CONCLUSIONS: Both intima and cap expressed novel genes not previously associated with SMC pathology. If the cap is derived from a unique subpopulation, this pattern is the signature of that particular set of cells. The loss of RGS5 in the fibrous cap is of particular interest because of its role in vessel development and physiology.

Carotid Arteries↗

PubMed2004

Regulator of G protein signaling 5 marks peripheral arterial smooth muscle cells and is downregulated in atherosclerotic plaque.

OBJECTIVE: Regulator of G protein signaling 5 (RGS5), an inhibitor of Galpha(q) and Galpha(i) activation, was recently identified among genes highly expressed in smooth muscle cells (SMCs) of aorta but not vena cava. This finding prompted the hypothesis that RGS5 provides long-term G protein inhibition specific to normal arterial SMC populations and that loss of expression may in turn contribute to arterial disease. METHODS: To test this hypothesis we characterized RGS5 gene expression throughout the vasculature of nonhuman primates to determine whether RGS5 was restricted to arteries in other vascular beds and whether expression was altered in arterial disease. RESULTS: In situ hybridization localized RGS5 message to medial SMCs of peripheral arteries, including carotid, iliac, mammary, and renal arteries, but not accompanying veins. SMCs of many small arteries and arterioles also expressed RGS5, including glomerular afferent arterioles critical to blood pressure regulation. Differential expression persisted in culture, inasmuch as RGS5 message was significantly higher in SMCs derived from arteries than from veins at real-time polymerase chain reaction. It was remarkable that the only major arterial bed lacking RGS5 was the coronary circulation. In atherosclerotic peripheral arteries RGS5 was expressed in medial SMCs, but was sharply downregulated in plaque SMCs. CONCLUSION: These data identify RGS5 as a new member of a short list of genes uniquely expressed in peripheral arteries but not coronary arteries. Persistence of an arterial pattern of RGS5 expression in culture and lack of expression in coronary arteries support a unique SMC phenotype fixed by distinct lineage or differentiation pathways. The association between loss of expression and arterial wall disease has prompted the new hypothesis that prolonged inhibition by RGS5 of vasoactive or trophic G protein signaling is critical to normal peripheral artery function.

Animals↗

PubMed2003

Suppression subtractive hybridization identifies distinctive expression markers for coronary and internal mammary arteries.

OBJECTIVE: We sought to identify differentially expressed genes in the athero-prone coronary artery and athero-resistant internal mammary arteries. METHODS AND RESULTS: Using suppressive subtraction hybridization, we generated reciprocal cDNA collections of representative mRNAs specific to porcine coronary arteries versus porcine mammary arteries. We screened 1000 suppressive subtraction hybridization cDNA clones by dot blot array and sequenced 600 of those showing the most marked expression differences. Northern blot, in situ hybridization, and immunostaining confirmed the differential gene expression patterns identified by the dot blot arrays. Genes associated with mammary arteries included claudin-10 and h-cadherin, which are genes associated with tight junctions and intermediate junctions. In contrast, genes associated with proatherosclerotic processes, such as lipid retention and metabolism, inflammation, and cell growth, were preferentially expressed in coronary arteries. CONCLUSIONS: Normal coronary arteries have gene expression program that is significantly different than internal mammary arteries. These differences may partly explain the resistance of coronary arteries and internal mammary arteries to atherosclerosis.

Animals↗

PubMed2003

Vascular failure: a hypothesis.

Although cardiac failure has been studied extensively, vascular failure is not a recognizable term. We suggest that it is reasonable to argue that failure of the vessel to control its mass, contractile capacity, and lumen will involve pathways similar to cardiac failure. Vascular failure, or perhaps more accurately arterial failure, has very different consequences. Failure to control mass and external diameter will result in hypertension or loss of lumen in atherosclerosis. We review what is known about this normal remodeling response and its failure, and propose directions for research.

Humans↗

PubMed2002

Expression profiling identifies 147 genes contributing to a unique primate neointimal smooth muscle cell phenotype.

OBJECTIVE: This study represents the first in an effort to systematically characterize different intimas by using expression array analysis. METHODS AND RESULTS: We compared smooth muscle cells (SMCs) of the neointima formed 4 weeks after aortic grafting with those from normal aorta and vena cava from cynomolgus monkeys. Hybridization to cDNA arrays identified subsets of 147 and 45 genes differentially expressed in the neointima versus the aorta and vena cava, respectively. The expression pattern differentiating neointima from aortic SMCs was characterized largely by suppression. Only 13 genes were induced in the neointima: 7 encoded matrix proteins (6 collagens and 1 versican) and 2 encoded inducers of matrix synthesis (osteoblast-specific factor-2/Cbfa1 and connective tissue growth factor). The genes suppressed most in the neointima included the regulator of G-protein signaling-5, SPARClike-1/hevin, and nonmuscle myosin heavy chain-B. A smaller gene set differentiated the neointima from the vena cava. Most were induced (39 of 45 genes), and overlap with the neointima-aorta set was significant (10 of 13 genes). Array results were validated with Northern analysis, in situ hybridization, or immunohistochemistry. CONCLUSIONS: These data underscore the importance of matrix synthesis in neointimal maturation, and novel genes, newly associated with neointimal SMCs (regulator of G-protein signaling-5 and osteoblast-specific factor-2/Cbfa1), have raised new hypotheses regarding the pathogenesis of intimal hyperplasia.

Animals↗