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Biomedical subjects

R Ross

Publications and source records attributed to R Ross.

At least 19 recordsLinked to original sources
PubMed1992

The extracellular glycoprotein SPARC interacts with platelet-derived growth factor (PDGF)-AB and -BB and inhibits the binding of PDGF to its receptors.

Interactions among growth factors, cells, and extracellular matrix are critical to the regulation of directed cell migration and proliferation associated with development, wound healing, and pathologic processes. Here we report the association of PDGF-AB and -BB, but not PDGF-AA, with the extracellular glycoprotein SPARC. Complexes of SPARC and 125I-labeled PDGF-BB or -AB were specifically immunoprecipitated by anti-SPARC immunoglobulins. 125I-PDGF-BB and -AB also bound specifically to SPARC that was immobilized on microtiter wells or bound to nitrocellulose after transfer from SDS/polyacrylamide gels. The binding of PDGF-BB to SPARC was pH-dependent; significant binding was detectable only above pH 6.6. The interaction of SPARC with specific dimeric forms of PDGF affected the activity of this mitogen. SPARC inhibited the binding of PDGF-BB and PDGF-AB, but not PDGF-AA, to human dermal fibroblasts in a dose-dependent manner. The expression of SPARC and PDGF was minimal in most normal adult tissues but was increased after injury. Enhanced expression of both PDGF-B chain and SPARC was seen in advanced lesions of atherosclerosis. We suggest that the coordinate expression of SPARC and PDGF-B-containing dimers following vascular injury may regulate the activity of specific dimeric forms of PDGF in vivo.

Animals↗
PubMed1992

Compartmentalization of PDGF on extracellular binding sites dependent on exon-6-encoded sequences.

The PDGFs are a family of molecules assembled as disulfide-bonded homo- and heterodimers from two distinct but highly homologous polypeptide chains (PDGF-A and PDGF-B). Two PDGF A-chain transcripts, which arise from alternative usage of the 69-bp exon 6 and exon 7, give rise to two forms of PDGF-A. In spite of the conservation of two PDGF A-chain forms over at least 350 million years, no differences in their biological activities have been identified. We have investigated the activity of the sequence encoded by the alternatively spliced exon 6 of the PDGF A-chain (peptide AL). Addition of peptide AL at 10(-5)-10(-9) M to cultured endothelium and smooth muscle induced a dose-dependent, 3-20-fold increase in PDGF in conditioned media within 30 min. Peptide AL had no detectable effect on A- or B-chain transcript levels, and decrease in culture temperature did not prevent rapid release of PDGF. In human umbilical vein endothelial cells treated with peptide AL, the PDGF release was principally PDGF-BB, while in smooth muscle cells it was primarily PDGF-AA. The capacity to induce release of PDGF is shared by the homologous peptide encoded by exon 6 of the B-chain of PDGF. Binding studies and cross-linking analysis are consistent with a charge-based association of exon 6 sequences with membrane- and matrix-associated heparan-sulfate proteoglycans. We hypothesize that translation of exon 6 of the A- or B-chain of PDGF results in compartmentalization of these forms of PDGF with HS-PG, whereas forms lacking this sequence would be soluble and diffuse.

Amino Acid Sequence↗
PubMed1992

Ontogeny of integumental calcium in relation to surface area and skin water content in the perinatal rat.

Calcium is an important regulator of epidermal differentiation and skin biomechanics in many vertebrate species. In this study, we measured total epidermal calcium in the perinatal Sprague-Dawley rat. Values ranged from 12 to 15 mg per 100 g of tissue. These levels were elevated compared with dermis and other soft (nonbone) organs, including brain, kidney, heart, and liver. Administration of radioactive calcium to the pregnant rat resulted in high rates of 45Ca2+ localization in the fetal epidermis 24 h later. From gestational day 20 to postnatal day 3, the epidermis showed progressive dehydration with water content decreasing from 79 to 73%. Dermal hydration over the same period decreased from 91 to 81%. In the neonatal rat (age 0-3 days), linear regression analysis of surface area vs. body weight on a log-log plot yielded a slope of 1.04. This finding contrasts with an expected slope of 0.67 based on simple surface area-to-volume relationships and differs from the empirical 0.75-power law observed in adult bioenergetics. In summary, these results show the perinatal rat is encapsulated by a continuous differentially hydrated calcium-rich epidermal envelope that increases in surface area over the early postnatal period directly as the first power of body mass.

Animals↗
PubMed1979

Platelets: cell proliferation and atherosclerosis.

Intimal smooth muscle proliferation is the hallmark of the lesions of atherosclerosis. Endothelial injury is postulated to precede this intimal smooth muscle proliferative response, which is mediated by a potent mitogenic factor derived from adherence, aggregation, and release by platelets at sites of endothelial injury. Smooth muscle proliferation is accompanied by varying amounts of connective tissue formation and intracellular and extracellular lipid deposition, dependent upon the risk factors encountered in each patient. The platelet-derived mitogen (PF) is a stable, cationic, relatively low molecular weight (10,000-30,000) protein that has been partially purified by ion exchange chromotography and gel filtration. Less than 100 ng of PF/ml culture medium can stimulate sparse 3T3 cells or smooth muscle cells, but not endothelial cells, to undergo multiple cell divisions in the presence of 5% cell-free, plasma-derived serum. The latter contains no mitogenic activity. The interaction of the platelet mitogen and plasma-derived components, including lipoproteins, plays a critical role in smooth muscle proliferation in vitro and in vivo in the induction of the lesions of atherosclerosis.

Animals↗
PubMed1979

The pathogenesis of atherosclerosis.

The pathogenesis of atherosclerosis is hypothesized to occur as a response to various forms of injury to the lining arterial endothelial cells. The resulting endothelial alterations could potentially lead to interactions between platelets in the circulation and the underlying subendothelial connective tissue or with the altered endothelial cells themselves. Such interactions provide an opportunity for platelet degranulation and release of a platelet-derived growth factor. This factor has been shown in cell culture to be an extremely potent mitogen and will induce DNA synthesis and cell multiplication of a number of cells including smooth muscle cells, fibroblasts, and other mesenchymally derived cells. Chronic endothelial injury and repeated interactions between platelet-derived mitogens, plasma components, and the underlying arterial smooth muslce cells would promote the progression of the intimal proliferative lesions of atherosclerosis that lead to the clinical sequelae associated with this disease process.

Animals↗
PubMed1978

Physiological quiescence in plasma-derived serum: influence of platelet-derived growth factor on cell growth in culture.

A platelet-derived growth factor can be shown to be the principal stimulant of DNA synthesis in whole blood serum for those cells that require serum for maintenance and growth in culture. Cell free plasma-derived serum lacks such platelet-derived material. 3T3 cells and primate arterial smooth muscle cells can be maintained in a quiescent state in culture for as long as six weeks in plasma-derived serum. Such cells can grow logarithmically after exposure to 5% whole blood serum or as little as 100 ng/ml of partially purified platelet factor. The cell cycle of smooth muscle cells has been studied in the quiescent (5% plasma-derived serum) and growing state (5% whole blood serum or 5% plasma-derived serum plus platelet factor). The generation time of smooth muscle cells is 16 to 18 hours as shown by autoradiographic frequency of labelled mitoses. The generation time is the same for cells in the growth fraction in either 5% whole blood serum or 5% plasma-derived serum. Thus, platelet factor acts by recruiting cells into the growth fraction rather than effecting a change in the duration of the cell cycle. Flow microfluorimetry studies on cells growing logarithmically in 5% whole blood serum give the following phase durations: G1 = 5.6 hours; S = 7.6 hours; and G2 + M = 3.8 hours. Based on these studies the argument is presented that cells cultured in 5% plasma-derived serum provide a more physiological base for the study of quiescence than do cells in low concentrations of whole blood serum or confluent, density inhibited cells at high (5% or greater) concentrations of whole blood serum. Furthermore, 5% plasma-derived serum represents an appropriate state to examine the perturbation of quiescent cells.

Animals↗
PubMed1978

Vessel injury, thrombosis, and platelet survival.

Vascular injury triggers platelet reactions of adhesion, aggregation, and release, and these reactions play important roles in hemostasis, thrombosis and thromboembolism, and atherogenesis. Measurement of platelet and fibrinogen turnover rates are indicators of the relative involvement of platelets and fibrin in the thrombotic process, and also provide an objective means of assessing antithrombotic therapy. Isotopic methods are preferred over chemical methods to measure platelet survival time; 51Cr is used most widely to label platelets. Problems of analysis and interpretation of platelet disappearance curves are reviewed briefly.

Animals↗
PubMed1978

Platelets, endothelium, and smooth muscle cells in atherosclerosis.

A factor derived from platelets stimulates the proliferation of smooth muscle cells in culture, and is likely important in stimulating smooth muscle proliferative lesions of atherogenesis in vivo. The platelet factor is produced during platelet aggregation when serum is made from whole blood. In vitro, smooth muscle cells are potent aggregating agents for platelets, while endothelial cells can inhibit this aggregating effect. Better understanding of the interactions of platelets, smooth muscle cells, and endothelium would facilitate developing effective means of intervening in or preventing the smooth muscle proliferative lesions of atherosclerosis.

Animals↗
PubMed1978

Coordinate control of 3T3 cell proliferation by platelet-derived growth factor and plasma components.

DNA synthesis and cell division were measured in Swiss mouse 3T3 cells cultured in different concentrations of cell-free plasma-derived serum and increasing amounts of a platelet-derived growth factor. In plasma-derived serum alone, the cells were quiescent and they were arrested in the Go/G1 phase of the cell cycle. Addition of a platelet-derived growth factor to quiescent cells maintained in plasma-derived serum stimulated both DNA synthesis and cell division. When plasma components were present at high concentration (5%, vol/vol), the amount of platelet factor added to the cultures determined the number of cell doublings. Plasma-derived molecules were required for the platelet factor to stimulate DNA synthesis and cell division in the maximal number of cells. In addition, plasma components had to be present for recently divided cells to respond to the platelet factor. When 3T3 cells were cultured in excess platelet factor and limiting amounts of plasma-derived serum (0.5%, vol/vol), the cells underwent one doubling and then ceased to proliferate. Addition of fresh plasma-derived serum to these cells induced a second round of cell division. Plasma components and the platelet-derived growth factor acted in a coordinate fashion to regulate the proliferation of Swiss 3T3 cells.

Blood Platelets↗
PubMed1978

Mediation of pinocytosis in cultured arterial smooth muscle and endothelial cells by platelet-derived growth factor.

Pinocytosis was measured in monkey aortic smooth muscle cells (SMC), bovine aortic endothelial cells, and Swiss 3T3 cells in culture as cellular uptake of [U-(14)C]sucrose and horseradish peroxidase (HRP) from the tissue culture medium. Monkey arterial SMC and Swiss 3T3 cells were maintained in a quiescent state of growth at low cells density in medium containing 5 percent monkey plasma-derived serum (PDS). Replacement of PDS with 5 percent monkey whole blood serum (WBS) from the same donor, or addition to PDS of partially purified platelet-derived growth factor(s) (PF), resulted in a marked stimulation of pinocytosis as well as of cellular proliferation. In SMC, enhancement of the rate of pinocytosis occurred 4-6 h after exposure to WBS or PF, and the rate was up to twofold higher than the rate in medium containing PDS. In contrast, [(3)H]thymidine uptake by SMC did not increase until 12-16 h after exposure to PF. In endothelial cells the presence of PF or WBS did not enhance either the rate of pinocytosis or the rate of proliferation over that in PDS. Thus, endothelial cells did not become quiescent at subconfluent densities in PDS but maintained rates of proliferation and pinocytosis that were equivalent to those in WBS. By autoradiography, the fraction of labeled nuclei in SMC cultures 24 h after change of medium increased from 0.061 +/- 0.004 in quiescent cultures to 0.313 +/- 0.028 after exposure to WBS or PF. In contrast, labeling indices of endothelial cells were similar for cultures grown in PDS, WBS, or PF at any single time point after change of medium. These findings suggest that the rate of pinocytosis maybe be coupled in some fashion to growth regulation, which may be mediated in part by specific growth factors, such as that derived from the thrombocyte.

Animals↗