Mohamad Irani-Tehrani

Bio: Mohamad Irani-Tehrani is an academic researcher from Scripps Research Institute. The author has contributed to research in topics: Endothelial stem cell & Cadherin. The author has an hindex of 4, co-authored 4 publications receiving 1583 citations.

A mechanosensory complex that mediates the endothelial cell response to fluid shear stress

Abstract: Shear stress is a fundamental determinant of vascular homeostasis, regulating vascular remodelling, cardiac development and atherogenesis, but the mechanisms of transduction are poorly understood. Previous work showed that the conversion of integrins to a high-affinity state mediates a subset of shear responses, including cell alignment and gene expression. Here we investigate the pathway upstream of integrin activation. PECAM-1 (which directly transmits mechanical force), vascular endothelial cell cadherin (which functions as an adaptor) and VEGFR2 (which activates phosphatidylinositol-3-OH kinase) comprise a mechanosensory complex. Together, these receptors are sufficient to confer responsiveness to flow in heterologous cells. In support of the relevance of this pathway in vivo, PECAM-1-knockout mice do not activate NF-kappaB and downstream inflammatory genes in regions of disturbed flow. Therefore, this mechanosensing pathway is required for the earliest-known events in atherogenesis.

A mechanosensory complex that mediates the endothelial cell response to fluid shear stress

Abstract: Shear stress is a fundamental determinant of vascular homeostasis, regulating vascular remodelling, cardiac development and atherogenesis, but the mechanisms of transduction are poorly understood. Previous work showed that the conversion of integrins to a high-affinity state mediates a subset of shear responses, including cell alignment and gene expression. Here we investigate the pathway upstream of integrin activation. PECAM-1 (which directly transmits mechanical force), vascular endothelial cell cadherin (which functions as an adaptor) and VEGFR2 (which activates phosphatidylinositol-3-OH kinase) comprise a mechanosensory complex. Together, these receptors are sufficient to confer responsiveness to flow in heterologous cells. In support of the relevance of this pathway in vivo, PECAM-1-knockout mice do not activate NF-kappaB and downstream inflammatory genes in regions of disturbed flow. Therefore, this mechanosensing pathway is required for the earliest-known events in atherogenesis.

VEGF receptor signalling - in control of vascular function.

Abstract: Vascular endothelial growth-factor receptors (VEGFRs) regulate the cardiovascular system. VEGFR1 is required for the recruitment of haematopoietic precursors and migration of monocytes and macrophages, whereas VEGFR2 and VEGFR3 are essential for the functions of vascular endothelial and lymphendothelial cells, respectively. Recent insights have shed light onto VEGFR signal transduction and the interplay between different VEGFRs and VEGF co-receptors in development, adult physiology and disease.

Effects of Disturbed Flow on Vascular Endothelium: Pathophysiological Basis and Clinical Perspectives

Abstract: Vascular endothelial cells (ECs) are exposed to hemodynamic forces, which modulate EC functions and vascular biology/pathobiology in health and disease. The flow patterns and hemodynamic forces are not uniform in the vascular system. In straight parts of the arterial tree, blood flow is generally laminar and wall shear stress is high and directed; in branches and curvatures, blood flow is disturbed with nonuniform and irregular distribution of low wall shear stress. Sustained laminar flow with high shear stress upregulates expressions of EC genes and proteins that are protective against atherosclerosis, whereas disturbed flow with associated reciprocating, low shear stress generally upregulates the EC genes and proteins that promote atherogenesis. These findings have led to the concept that the disturbed flow pattern in branch points and curvatures causes the preferential localization of atherosclerotic lesions. Disturbed flow also results in postsurgical neointimal hyperplasia and contributes to pathophysiology of clinical conditions such as in-stent restenosis, vein bypass graft failure, and transplant vasculopathy, as well as aortic valve calcification. In the venous system, disturbed flow resulting from reflux, outflow obstruction, and/or stasis leads to venous inflammation and thrombosis, and hence the development of chronic venous diseases. Understanding of the effects of disturbed flow on ECs can provide mechanistic insights into the role of complex flow patterns in pathogenesis of vascular diseases and can help to elucidate the phenotypic and functional differences between quiescent (nonatherogenic/nonthrombogenic) and activated (atherogenic/thrombogenic) ECs. This review summarizes the current knowledge on the role of disturbed flow in EC physiology and pathophysiology, as well as its clinical implications. Such information can contribute to our understanding of the etiology of lesion development in vascular niches with disturbed flow and help to generate new approaches for therapeutic interventions.

Mechanotransduction at a distance: mechanically coupling the extracellular matrix with the nucleus

Abstract: Research in cellular mechanotransduction often focuses on how extracellular physical forces are converted into chemical signals at the cell surface. However, mechanical forces that are exerted on surface-adhesion receptors, such as integrins and cadherins, are also channelled along cytoskeletal filaments and concentrated at distant sites in the cytoplasm and nucleus. Here, we explore the molecular mechanisms by which forces might act at a distance to induce mechanochemical conversion in the nucleus and alter gene activities.

Cellular mechanotransduction: putting all the pieces together again.

Abstract: Analysis of cellular mechanotransduction, the mechanism by which cells convert mechanical signals into biochemical responses, has focused on identification of critical mechanosensitive molecules and cellular components. Stretch-activated ion channels, caveolae, integrins, cadherins, growth factor receptors, myosin motors, cytoskeletal filaments, nuclei, extracellular matrix, and numerous other structures and signaling molecules have all been shown to contribute to the mechanotransduction response. However, little is known about how these different molecules function within the structural context of living cells, tissues, and organs to produce the orchestrated cellular behaviors required for mechanosensation, embryogenesis, and physiological control. Recent work from a wide range of fields reveals that organ, tissue, and cell anatomy are as important for mechanotransduction as individual mechanosensitive proteins and that our bodies use structural hierarchies (systems within systems) composed of interconnected networks that span from the macroscale to the nanoscale in order to focus stresses on specific mechanotransducer molecules. The presence of isometric tension (prestress) at all levels of these multiscale networks ensures that various molecular scale mechanochemical transduction mechanisms proceed simultaneously and produce a concerted response. Future research in this area will therefore require analysis, understanding, and modeling of tensionally integrated (tensegrity) systems of mechanochemical control.