The Role of the Endothelium in HPS Pathogenesis and Potential Therapeutic Approaches

Abstract

<jats:p>American hantaviruses cause a highly lethal acute pulmonary edema termed hantavirus pulmonary syndrome (HPS). Hantaviruses nonlytically infect endothelial cells and cause dramatic changes in barrier functions of the endothelium without disrupting the endothelium. Instead hantaviruses cause changes in the function of infected endothelial cells that normally regulate fluid barrier functions of capillaries. The endothelium of arteries, veins, and lymphatic vessels is unique and central to the function of vast pulmonary capillary beds, which regulate pulmonary fluid accumulation. The endothelium maintains vascular barrier functions through a complex series of redundant receptors and signaling pathways that serve to both permit fluid and immune cell efflux into tissues and restrict tissue edema. Infection of the endothelium provides several mechanisms for hantaviruses to alter capillary permeability but also defines potential therapeutic targets for regulating acute pulmonary edema and HPS disease. Here we discuss interactions of HPS causing hantaviruses with the endothelium, potential endothelial cell-directed permeability mechanisms, and therapeutic targeting of the endothelium as a means of reducing the severity of HPS disease.</jats:p>

Hypoxia Induces Permeability and Giant Cell Responses of Andes Virus-Infected Pulmonary Endothelial Cells by Activating the mTOR-S6K Signaling Pathway

“…Hypoxia and ANDV infection enhance the formation of giant MECs and LECs. The ability of ANDV infection to cause the formation of giant LECs in response to VEGF was previously reported and suggested to be regulated by rapamycin-sensitive mTOR signaling responses (41). Combined with the results presented above, these findings suggested that hypoxic conditions might be sufficient to increase the size of ANDV-infected MECs and LECs.…”

“…Consistent with hantavirus inactivation of ␣ v ␤ 3 , the knocking out of ␤ 3 or inhibition of ␣ v ␤ 3 promotes VEGFR2-directed endothelial cell permeability (56)(57)(58)(59)(60). A recent report further demonstrated that ANDV infects lymphatic endothelial cells (LECs) and both enhances LEC permeability and causes the formation of giant LECs in response to VEGF (41,47). These findings indicate that both microvascular leakage and pulmonary fluid clearance by lymphatic vessels are likely to be altered by ANDV infection of MECs and LECs.…”

“…In fact, the pulmonary edema fluid of HPS patients contains high levels of VEGF (40,41). VEGF was originally named "vascular permeability factor" for its potent ability to induce tissue edema ϳ50,000 times more effectively than histamine (38,42).…”

“…In vitro, pulmonary microvascular endothelial cells (MECs) and human umbilical vein endothelial cells (HUVECs) are not permeabilized by hantavirus infection alone; however, the permeability of endothelial cells infected by ANDV, SNV, and NY-1V, but not nonpathogenic Tula virus (TULV) or PHV hantaviruses, is dramatically enhanced in response to VEGF (41,(47)(48)(49)(50)(51)(52). Days after infection, cell-associated pathogenic hantaviruses bind inactive ␣ v ␤ 3 integrins which normally temper VEGFR2 responses (48,50,(53)(54)(55).…”

“…Days after infection, cell-associated pathogenic hantaviruses bind inactive ␣ v ␤ 3 integrins which normally temper VEGFR2 responses (48,50,(53)(54)(55). This results in both hyperphosphorylation of VEGFR2 and increases in the VEGFR2 signaling responses that direct the dissociation and internalization of VE-cadherin from adherens junctions without VE-cadherin degradation (41,47,48,(50)(51)(52). The internalization of VE-cadherin without degradation permits the rapid reassembly of adherens junctions and participates in the rapid ability of the endothelium to increase fluid barrier functions (34,37).…”