The overall aim of this proposal is to demonstrate the physiologic function of factor XII (XII) and prolylcarboxypeptidase (PRCP) on angiogenesis, vascular signaling pathways, arterial thrombosis risk, or hypertension. The overall hypothesis of this proposal is that factor XII and prolycarboxypeptidase modulate vascular function and arterial thrombosis risk in vivo. Preliminary studies indicate that factor XII (XII) has an outside-in signaling pathway mediated by uPAR that is blocked by high molecular weight kininogen (HK) that leads to cell proliferation, growth, and angiogenesis. Furthermore, prolylcarboxypeptidase (PRCP), an endothelial cell plasma prekallikrein activator, influences constitutive arterial thrombosis risk and blood pressure in vivo. PRCP murine hypomorphs are lean, prothrombotic and hypertensive. Our data indicate that XII regulates angiogenesis through an outside-in signaling pathways and that reduced prolylcarboxypeptidase in a murine hypomorphs increases arterial thrombosis risk associated with hypertension in the intravascular compartment.
The specific aims of this proposal follow:
Specific Aim 1 : The outside-in signaling mechanism(s) of XII through uPAR and the EGFR on endothelial cells will be elucidated to characterize its pathway(s) leading to angiogenesis. The hypothesis of this specific aim is that XII stimulates endothelial cell signaling, growth and angiogenesis to promote vascular growth after injury.
This specific aim will examine the following questions: 1) Characterize angiogenesis defects in XII KO mice and determine XII's contribution to the repair mechanisms after vascular injury. 2) Determine the mechanism(s) by which XII interacts with the EGFR on endothelial cells and determine this pathway's influence on angiogenesis and injury repair processes.
Specific Aim 2 : The mechanism(s) by which PRCP contributes to reduced thrombosis risk and blood pressure in vivo will be characterized. The hypothesis of this specific aim is that PRCP reduces arterial thrombosis risk and lowers blood pressure by reducing tissue reactive oxygen species.
This specific aim will examine the following questions: 1) Determine the mechanism(s) by which reduced PRCP in murine hypomorphs results in increased reactive oxygen species and eNOS uncoupling leading to its prothrombotic and hypertensive state. 2) Determine if the mechanism(s) for hypertension and thrombosis risk in the PRCP murine hypomorphs are linked. 3) Determine if reduced PRCP metabolism of a-melanocyte stimulating hormone contributes to PRCP murine hypomorphs'prothrombotic and hypertensive phenotype.
The specific aims of this proposal are derived from observations on how XII influences endothelial cell signaling, growth, and angiogenesis and the phenotypes of the newly created PRCP murine hypomorph. The XII signaling pathway leads to in vitro and in vivo angiogenesis. PRCP modulates arterial thrombosis risk and blood pressure. The PRCP murine hypomorphs have shortened times to arterial thrombosis and are constitutively hypertensive. New evidence indicates increased reactive oxygen species and peroxynitrite and uncoupled eNOS in their arterial vessels. The increased arterial thrombosis risk is corrected with treatment with the antioxidant Tempol. In vitro and in vivo investigations on XII and PRCP may indicate new therapeutic targets to modulate arterial thrombosis and hypertension without increasing bleeding risk.
This project aims to characterize the physiologic activities of factor XII (XII) and prolylcarboxypeptidase (PRCP). XII has an outside-in signaling system through uPAR that results in cell growth, proliferation, and angiogenesis. XII KO mice have reduced angiogenesis. This project aims to characterize the physiologic angiogenic activity of XII and characterize its signaling pathway through the EGFR. PRCP hypomorphs are prothrombotic and hypertensive. We found that these mice have increased reactive oxygen species, peroxynitrite, and uncoupled eNOS. Furthermore, antioxidant therapy with Tempol corrects the prothrombotic risk. The proposal aims to characterize the first recognized prothrombotic mouse due to increased reactive oxygen therapy. Studies will also examine if the prothrombotic and hypertensive mechanisms are linked.
|Stavrou, Evi X; Fang, Chao; Bane, Kara L et al. (2018) Factor XII and uPAR upregulate neutrophil functions to influence wound healing. J Clin Invest 128:944-959|
|Schmaier, A H (2016) The contact activation and kallikrein/kinin systems: pathophysiologic and physiologic activities. J Thromb Haemost 14:28-39|
|Jaffa, Miran A; Luttrell, Deirdre; Schmaier, Alvin H et al. (2016) Plasma Prekallikrein Is Associated With Carotid Intima-Media Thickness in Type 1 Diabetes. Diabetes 65:498-502|
|Schmaier, Alvin H (2016) Antithrombotic potential of the contact activation pathway. Curr Opin Hematol 23:445-52|
|Stavrou, Evi X; Fang, Chao; Merkulova, Alona et al. (2015) Reduced thrombosis in Klkb1-/- mice is mediated by increased Mas receptor, prostacyclin, Sirt1, and KLF4 and decreased tissue factor. Blood 125:710-9|
|Wang, Yunmei; Fang, Chao; Gao, Huiyun et al. (2014) Platelet-derived S100 family member myeloid-related protein-14 regulates thrombosis. J Clin Invest 124:2160-71|
|Schmaier, Alvin H (2014) Extracorporeal circulation without bleeding. Sci Transl Med 6:222fs7|
|Wang, J; Matafonov, A; Madkhali, H et al. (2014) Prolylcarboxypeptidase independently activates plasma prekallikrein (fletcher factor). Curr Mol Med 14:1173-85|
|Schmaier, Alvin H (2014) Physiologic activities of the contact activation system. Thromb Res 133 Suppl 1:S41-4|
|Adams, Gregory N; Stavrou, Evi X; Fang, Chao et al. (2013) Prolylcarboxypeptidase promotes angiogenesis and vascular repair. Blood 122:1522-31|
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