Regulation of Cellular Redox Signaling by Matricellular Proteins in Vascular Biology, Immunology, and Cancer

Abstract

Significance: In contrast to structural elements of the extracellular matrix, matricellular proteins appear transiently during development and injury responses, but their sustained expression can contribute to chronic disease. Through interactions with other matrix components and specific cell surface receptors, matricellular proteins regulate multiple signaling pathways, including those mediated by reactive oxygen and nitrogen species and H 2 S. Dysregulation of matricellular proteins contributes to the pathogenesis of vascular diseases and cancer. Defining the molecular mechanisms and receptors involved is revealing new therapeutic opportunities. Recent Advances: Thrombospondin-1 (TSP1) regulates NO, H 2 S, and superoxide production and signaling in several cell types. The TSP1 receptor CD47 plays a central role in inhibition of NO signaling, but other TSP1 receptors also modulate redox signaling. The matricellular protein CCN1 engages some of the same receptors to regulate redox signaling, and ADAMTS1 regulates NO signaling in Marfan syndrome. In addition to mediating matricellular protein signaling, redox signaling is emerging as an important pathway that controls the expression of several matricellular proteins. Critical Issues: Redox signaling remains unexplored for many matricellular proteins. Their interactions with multiple cellular receptors remains an obstacle to defining signaling mechanisms, but improved transgenic models could overcome this barrier. Future Directions: Therapeutics targeting the TSP1 receptor CD47 may have beneficial effects for treating cardiovascular disease and cancer and have recently entered clinical trials. Biomarkers are needed to assess their effects on redox signaling in patients and to evaluate how these contribute to their therapeutic efficacy and potential side effects. Antioxid. Redox Signal. 27, 874-911.

Microcirculation Evaluation of Leg Ulcers - An Innovative Diagnostic Approach

“…systems able to perpetuate the Chronicity of inflammation, and further acquisitions on cellularity (chemo-taxis, macrophages and monocytes) demonstrate their complex interconnection that makes it still difficult to univocally explain the processes involved respectively at the cellular level, intercellular and with the extracellular matrix [5][6][7]. Biofilms, ROS / NOS systems [8][9][10][11][12][13], microvesicles [14,15], metalloproteases [3][4][5] and other factors have been examined and are sometimes held responsible for the transformation of the acute inflammatory state into chronic [14][15][16][17][18][19][20]. Only the presence of the infection in bio film form and the ability of the latter to modify the host's reaction appear to be able to provide a plausible explanation, but not all ulcers are infected and not all are found of biofilm [21,22].…”

Extracellular Matrix and Redox Signaling in Cellular Responses to Stress

“…Hypoxia and fluid shear stress activate NOS3 to increase blood flow, and adrenergic tone opposes this vasodilator activity of NO to maintain physiological blood pressure. Studies using mice lacking thrombospondin-1 or CD47 demonstrated a physiological role for CD47 signaling to limit both NO biosynthesis and cGMP-mediated signaling pathways controlled by NO in the vasculature (9). Thrombospondin-1 accumulates in the vasculature in response to ischemic injuries and several chronic diseases of aging, thereby limiting NO signaling and tissue perfusion.…”

“…Two articles in this Forum review physiological and Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. pathophysiological functions of this pathway and the potential to therapeutically suppress CD47 signaling to restore NO signaling in acute ischemic injuries, cardiovascular disease, and aging (5,9).…”

“…Studies of other matricellular proteins are also discussed that demonstrate regulation of inducible NOS (NOS2) as well as NOS3-mediated NO synthesis by matricellular proteins, and the ability of matricellular proteins to control ROS and H 2 S signaling as well as NO signaling (9). CD47 signaling limits the autocrine induction of H 2 S biosynthesis and signaling that supports T cell activation, and thrombospondin-1 signaling through CD47 inhibits T cell activation.…”

“…Ongoing studies are also exploring therapeutic applications of drugs targeting specific matricellular protein receptors to correct the dysregulation of redox signaling in several diseases. Antibody or antisense blockade of thrombospondin-1 signaling through CD47 protects mice from a variety of ischemic injuries by increasing NO/cGMP signaling and preserves resistance to these injuries in aging mice (9). This strategy could overcome the resistance to NOdonating drugs associated with diseases of aging.…”