חיפוש מתקדם

J. D. Rojas, S. R. Sennoune, D. Maiti, K. Bakunts, S. C. Sanka, G. M. Martinez, E. A. Seftor, C. J. Meininger, G. Wu, D. E. Wesson, M. J. C. Hendrix, and R. Martínez-Zaguilán

Microvascular endothelial cells involved in angiogenesis are exposed to an acidic environment that is not conducive for growth and survival. These cells must exhibit a dynamic intracellular (cytosolic) pH (pHcyt) regulatory mechanism to cope with acidosis, in addition to the ubiquitous Na+/H+ exchanger and HCO3-based H+-transporting systems. We hypothesize that the presence of plasmalemmal vacuolar-type proton ATPases (pmV-ATPases) allows microvascular endothelial cells to better cope with this acidic environment and that pmV-ATPases are required for cell migration. This study indicates that microvascular endothelial cells, which are more migratory than macrovascular endothelial cells, express pmV-ATPases. Spectral imaging microscopy indicates a more alkaline pHcyt at the leading than at the lagging edge of microvascular endothelial cells. Treatment of microvascular endothelial cells with V-ATPase inhibitors decreases the proton fluxes via pmV-ATPases and cell migration. These data suggest that pmV-ATPases are essential for pHcyt regulation and cell migration in microvascular endothelial cells.

endothelial cells are uniquely positioned within vessels of the macro- and microcirculation. Macro- and microvascular endothelial cells play an important role in regulating blood vessel tone and blood flow by synthesizing and secreting paracrine and autocrine growth factors and hormones (1015). Endothelial cells also secrete proteolytic enzymes, which are needed for formation of new capillary networks, a necessary step in vascular remodeling (13).

Changes in intracellular (cytosolic) pH (pHcyt) are important in signal transduction mechanisms, which regulate many physiological processes, including cell growth, secretion, contraction, and invasion/migration (184447). These processes are important in angiogenesis and vascular remodeling (13). The regulation of pHcyt in most eukaryotic cells, including endothelial cells, is mediated by the Na+/H+ exchanger and HCO3-dependent H+-transporting mechanisms (11172268). In some specialized and highly invasive cells (metastatic cells, macrophages, neutrophils, and osteoclasts), plasma membrane vacuolar (V) H+-ATPases (pmV-ATPases) are also used to regulate pHcyt (27355058). These ATPases are distinguished from other proton pumps by their pharmacological inhibition (833). The V-ATPases are inhibited by bafilomycin A1, concanamycin, salicylihalamide, and 7-chloro-4-dinitrobenz-2-oxa-1,3-diazole, which have no effect on the P- or F-type ATPases (69526465).

Microvascular endothelial cells, similar to tumor cells, are exposed to hypoxic and acidic environments (3160), which are not favorable for growth and cell survival. We have shown that pmV-ATPase expression in highly invasive metastatic tumor cells provides a dynamic pHcyt regulatory mechanism for these cells (2751). The similarity between metastatic cells and angiogenic microvascular endothelial cells with regard to invasion of adjacent tissue by the invading cell led us to hypothesize that 1) microvascular, but not macrovascular, endothelial cells express pmV-ATPase as a dynamic pHcyt regulatory mechanism, which allows them to cope with acidic environments, 2) microvascular endothelial cells employ this pump's activity for cell migration, and 3) the presence of pmV-ATPases at the leading edge in microvascular endothelial cells allows them to maintain a more alkaline pHcyt at the leading than at the lagging edge, thus creating a pHcyt gradient favorable for cell migration.

P. H1147-H1157

פותח על ידי קלירמאש פתרונות בע"מ -
הספר "אוצר וולקני"
אודות
תנאי שימוש
Vacuolar Type H+ -ATPases at the Plasma Membrane Regulate pH and Cell Migration in Microvascular Endothelial Cells
291 (3)

J. D. Rojas, S. R. Sennoune, D. Maiti, K. Bakunts, S. C. Sanka, G. M. Martinez, E. A. Seftor, C. J. Meininger, G. Wu, D. E. Wesson, M. J. C. Hendrix, and R. Martínez-Zaguilán

Vacuolar Type H+ -ATPases at the Plasma Membrane Regulate pH and Cell Migration in Microvascular Endothelial Cells

Microvascular endothelial cells involved in angiogenesis are exposed to an acidic environment that is not conducive for growth and survival. These cells must exhibit a dynamic intracellular (cytosolic) pH (pHcyt) regulatory mechanism to cope with acidosis, in addition to the ubiquitous Na+/H+ exchanger and HCO3-based H+-transporting systems. We hypothesize that the presence of plasmalemmal vacuolar-type proton ATPases (pmV-ATPases) allows microvascular endothelial cells to better cope with this acidic environment and that pmV-ATPases are required for cell migration. This study indicates that microvascular endothelial cells, which are more migratory than macrovascular endothelial cells, express pmV-ATPases. Spectral imaging microscopy indicates a more alkaline pHcyt at the leading than at the lagging edge of microvascular endothelial cells. Treatment of microvascular endothelial cells with V-ATPase inhibitors decreases the proton fluxes via pmV-ATPases and cell migration. These data suggest that pmV-ATPases are essential for pHcyt regulation and cell migration in microvascular endothelial cells.

endothelial cells are uniquely positioned within vessels of the macro- and microcirculation. Macro- and microvascular endothelial cells play an important role in regulating blood vessel tone and blood flow by synthesizing and secreting paracrine and autocrine growth factors and hormones (1015). Endothelial cells also secrete proteolytic enzymes, which are needed for formation of new capillary networks, a necessary step in vascular remodeling (13).

Changes in intracellular (cytosolic) pH (pHcyt) are important in signal transduction mechanisms, which regulate many physiological processes, including cell growth, secretion, contraction, and invasion/migration (184447). These processes are important in angiogenesis and vascular remodeling (13). The regulation of pHcyt in most eukaryotic cells, including endothelial cells, is mediated by the Na+/H+ exchanger and HCO3-dependent H+-transporting mechanisms (11172268). In some specialized and highly invasive cells (metastatic cells, macrophages, neutrophils, and osteoclasts), plasma membrane vacuolar (V) H+-ATPases (pmV-ATPases) are also used to regulate pHcyt (27355058). These ATPases are distinguished from other proton pumps by their pharmacological inhibition (833). The V-ATPases are inhibited by bafilomycin A1, concanamycin, salicylihalamide, and 7-chloro-4-dinitrobenz-2-oxa-1,3-diazole, which have no effect on the P- or F-type ATPases (69526465).

Microvascular endothelial cells, similar to tumor cells, are exposed to hypoxic and acidic environments (3160), which are not favorable for growth and cell survival. We have shown that pmV-ATPase expression in highly invasive metastatic tumor cells provides a dynamic pHcyt regulatory mechanism for these cells (2751). The similarity between metastatic cells and angiogenic microvascular endothelial cells with regard to invasion of adjacent tissue by the invading cell led us to hypothesize that 1) microvascular, but not macrovascular, endothelial cells express pmV-ATPase as a dynamic pHcyt regulatory mechanism, which allows them to cope with acidic environments, 2) microvascular endothelial cells employ this pump's activity for cell migration, and 3) the presence of pmV-ATPases at the leading edge in microvascular endothelial cells allows them to maintain a more alkaline pHcyt at the leading than at the lagging edge, thus creating a pHcyt gradient favorable for cell migration.

P. H1147-H1157

Scientific Publication
You may also be interested in