Although proteoglycans constitute a minor component of vascular tissue, these molecules have been shown to influence a number of arterial properties such as viscoelasticity, permeability, lipid metabolism, hemostasis, and thrombosis. A hallmark of early and late atherosclerosis is the accumulation of proteoglycans in the intimal lesions. Yet, it is not clear why this accumulation occurs. This article reviews the classes of proteoglycans synthesized by the two major cell types of the arterial wall--the endothelial and smooth muscle cell. Detailed consideration is then given to the modulation of proteoglycan metabolism and the role that proteoglycans play in a number of cellular events such as adhesion, migration, and proliferation--important processes in both the development and the pathogenesis of blood vessels. Last, the involvement of proteoglycans in two critical vascular wall processes--hemostasis and lipid metabolism--is reviewed, because these events pertain to atherogenesis. This review emphasizes the importance of proteoglycans in regulating several key events in normal and pathophysiological processes in the vascular tissue.

Cell biology of arterial proteoglycans.

Elastic fibres and vascular structure in hypertension

Inflammation is involved in pathogenesis of hypertension. NLRP3 inflammasome activation is a powerful mediator of inflammatory response via caspase-1 activation. The present study was designed to determine the roles and mechanisms of NLRP3 inflammasome in phenotypic modulation and proliferation of vascular smooth muscle cells (VSMCs) in hypertension. Experiments were conducted in spontaneously hypertensive rats (SHR) and primary aortic VSMCs. NLRP3 inflammasome activation was observed in the media of aorta in SHR and in the VSMCs from SHR. Knockdown of NLRP3 inhibited inflammasome activation, VSMC phenotypic transformation and proliferation in SHR-derived VSMCs. Increased NFκB activation, histone acetylation and histone acetyltransferase expression were observed in SHR-derived VSMCs and in media of aorta in SHR. Chromatin immunoprecipitation analysis revealed the increased histone acetylation, p65-NFκB and Pol II occupancy at the NLRP3 promoter in vivo and in vitro. Inhibition of NFκB with BAY11-7082 or inhibition of histone acetyltransferase with curcumin prevented the NLRP3 inflammasome activation, VSMC phenotype switching and proliferation in VSMCs from SHR. Moreover, curcumin repressed NFκB activation. Silencing of NLRP3 gene ameliorated hypertension, vascular remodeling, NLRP3 inflammasome activation and phenotype switching in the aorta of SHR. These results indicate that NLRP3 inflammasome activation response to histone acetylation and NFκB activation contributes to VSMC phenotype switching and proliferation and vascular remodeling in hypertension.

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NLRP3 inflammasome activation contributes to VSMC phenotypic transformation and proliferation in hypertension.

The arterial wall contains a significant amount of charged proteoglycans, which are inhomogeneously distributed, with the greatest concentrations in the intimal and medial layers. The hypothesis of...

Heterogeneous transmural proteoglycan distribution provides a mechanism for regulating residual stresses in the aorta

Background: Four distinguishing histopathological characteristics of thoracic aortic aneurysms and dissections (TAADs) are the fragmentation or degradation of elastic fibers, loss of smooth muscle, pooling of glycosaminoglycans, and remodeling of fibrillar collagens. Of these, pooling of glycosaminoglycans appears to be unique to these lesions. Methods: This review acknowledges the importance of dysregulated transforming growth factor-β (TGF-β) in TAADs and offers a complementary hypothesis that increased TGF-β could contribute to the accumulation of glycosaminoglycans in the media of the proximal thoracic aorta. Regardless, observed pools of glycosaminoglycans could decrease tensile strength, cause stress concentrations, and increase intralamellar swelling pressure, all of which could initiate local delaminations that could subsequently propagate as dissections and result in a false lumen or rupture. Conclusions: There is a pressing need to investigate potential mechanical as well as biological consequences of accumulated glycosaminoglycans in TAADs and to elucidate responsible signaling pathways, with particular attention to synthetic cells of nonmesodermal lineage. Such research could provide insight into the mechanisms of dissection and the seemingly paradoxical role of the over-expression of a cytokine that is typically associated with fibrosis but is implicated in a degenerative disease of the aorta that can result in a catastrophic mechanical failure.

/pdf/possible-mechanical-roles-of-glycosaminoglycans-in-thoracic-4e0pukj0sc.pdf

Possible Mechanical Roles of Glycosaminoglycans in Thoracic Aortic Dissection and Associations with Dysregulated Transforming Growth Factor-β

The extracellular matrix of blood vessel walls contains elastin, collagen, and proteoglycans, all of which can affect vascular resistance and, hence, blood pressure by virtue of their biomechanical properties.In the present study, we have begun to explore the possibility that proteoglycans may play a role in the pathophysiology of hypertension by analyzing, qualitatively and quantitatively, the polysaccharide components of proteoglycans from aorta of two normotensive rat strains, Wistar Kyoto (WKY) and Wistar rats, and from spontaneously hypertensive (SH) rats of the Okamoto strain.The total concentration of aorta glycosaminoglycans in the SH rat was 33% higher than in the WKY rat, due to a 164% increase in chondroitin 4- and 6-sulfate.The content of dermatan sulfate (DS), hyaluronic acid (HA), and heparan sulfate (HS) was similar in the two strains.The 4-wk-old SH rat also had an increase in chondroitin sulfate (CS) compared to the 4-wk-old WKY rat, without any change in DS, HA, or HS.The Wistar rat had approximately the same concentration of CS and DS in the aorta as the WKY rat, but HS and HA were reduced by 62 and 37%, respectively.The galactosaminoglycans (CS and DS) were heterogeneous on cellulose acetate electrophoresis and exhibited a different pattern for each of the three strains.Undersulfated CS accounted for 15 % of the total CS in WKY aorta but was present in only trace amounts in the SH aorta; 2% of the CS from the Wistar aorta was undersulfated.In all three strains, DS was exclusively 4-sulfated, and the CS contained approximately equal amounts of 4- and 6-sulfated galactosamine residues.Ultrastructural studies demonstrated that the HS was localized in the subendothelial matrix and the pericellular region surrounding the medial smooth muscle cells.CS and DS were primarily associated with collagen in the media.In the SH rat aorta the subendothelial matrix was thicker, and there was a relative increase in the CS/DS in the smooth muscle cell pericellular matrix.We suggest that, if similar alterations in CS proteoglycans are present in the resistance vessels, these changes may contribute to the increased peripheral vascular resistance in the hypertensive animal.

Proteoglycans and hypertension. I. A biochemical and ultrastructural study of aorta glycosaminoglycans in spontaneously hypertensive rats.

Spontaneously hypertensive (SH) rats are known to have an increased content of chondroitin sulfate (CS) proteoglycans (PG) in the aorta as compared to normotensive Wistar Kyoto (WKY) rats. In the present study we have compared WKY and SH rat aortas with respect to [35S]sulfate incorporation in vivo and in vitro. The specific activity (cpm/mg aorta) of the total glycosaminoglycan (GAG) pool from SH rat aorta, measured 48 h after intraperitoneal injection of [35S]sulfate, was twice as high as that of WKY aorta GAG. After in vitro incubation of aortas for 4 or 6 h, the specific activity (cpm/mg aorta) of glycosaminoglycans from SH rat was 2.4- to 7.1-fold higher than in controls. Labeled PG were extracted with 4 M guanidine from aortas which had been incubated with [35S]sulfate, and chromatography of the extract on Sepharose CL-6B yielded two incompletely resolved peaks, one emerging with the void volume (peak I) and one in a more retarded position (peak II). Peak I (WKY) contained nearly equal amounts of CS and HS (53 and 46%, respectively) and a small amount of DS (8%). Peak II (WKY) (Kav, 0.34) was divided into two fractions; the fraction of larger molecular weight (II A) contained 43% CS, 35% DS, and 20% HS, whereas the smaller fraction (II B) contained 40% CS, 51% DS, and 5% HS. In each corresponding pool from SH rat aorta, a similar proportion of HS was found, but the DS content was approximately half, and the CS content was correspondingly greater. The estimated molecular weights of the CS/DS chains in peaks I, II A, and II B from WKY aorta were 34,600, 18,800, and 11,600 daltons, respectively, whereas the corresponding values for the SH rat aorta pools were 32,300, 24,700, and 17,000 daltons, respectively. The proportions of 4- and 6-sulfated galactosamine residues as well as the degree of sulfation of the CS/DS PG were similar in the two strains. The HS-PG was larger in the WKY rat aorta and was made up of larger HS chains (Mr 26,600 vs. 16,100); however, the degree of sulfation was apparently similar in the two strains. These results suggest that the rates of PG synthesis and/or degradation and the PG structure are altered in the SH rat aorta.

Richard H. Reynertson

Papers

Proteoglycans and hypertension. I. A biochemical and ultrastructural study of aorta glycosaminoglycans in spontaneously hypertensive rats.

Proteoglycans and Hypertension II.[35S]Sulfate Incorporation into Aorta Proteoglycans of Spontaneously Hypertensive Rats

Oligosaccharide substrates for heparin sulfamidase

Proteoglycans and Hypertension: III: Aorta Proteoglycans in Dahl Salt-Sensitive Hypertensive Rats

Rapid and specific assay of collagen glucosyltransferase with a Sepharose-bound substrate