Fever-range hyperthermia and disturbed flow disrupt the arterial endothelial barrier via IRE1Α-XBP1-dependent autophagy

The National Institute of General Medical Sciences awarded Nova Southeastern University, Inc. $144,800 for a project grant (NIGMS R16GM166725) on September 1, 2026, under the Biomedical Research and Research Training program (CFDA 93.859).

The award funds research into how fever-range hyperthermia and disturbed blood flow disrupt arterial endothelial barriers through IRE1α-XBP1-dependent autophagy. The research combines in vitro studies using a bioreactor system to simulate physiological shear stress and thermal conditions with in vivo studies in mice to map endothelial barrier disruption across laminar and disturbed-flow regions of the vasculature. The work tests whether genetic knockdown or pharmacologic inhibition of IRE1α can restore vascular endothelial cadherin junction integrity and preserve barrier function during febrile illness.

Performance takes place in Davie, Florida, with a period of performance from September 1, 2026, through August 31, 2030.

Abstract

The arterial endothelium is a critical single-cell barrier that maintains vascular integrity and regulates molecular exchange. When this barrier fails, plasma leaks into the arterial wall, triggering inflammation that contributes to myocardial infarction and stroke. Fever-range hyperthermia (FRH, defined as 39-41 c) and disturbed blood flow (d-flow), particularly at arterial branch points, are independent stressors known to compromise endothelial function. In clinical scenarios such as sepsis or autoimmune flare, systemic fever often coincides with atheroprone regions, subjecting the vasculature to compounded thermal and hemodynamic stress. Despite its relevance, the magnitude, spatial distribution, and molecular mechanisms of this dual insult remain poorly understood, limiting strategies to preserve vascular integrity during febrile illness. Our preliminary data show that FRH combined with oscillatory shear stress disrupts vascular endothelial cadherin (VE-cadherin) junctions more severely than either stressor alone. These findings support our central hypothesis that FRH activates the inositol-requiring enzyme 1 alpha-x-box binding protein 1 (IRE1Α-XBP1) arm of the unfolded protein response to induce autophagy, destabilizing endothelial junctions, with d-flow amplifying this injury. To test this, aim 1 will define the interaction between FRH and d-flow in vitro using a bioreactor system to simulate physiological shear and thermal conditions. We will quantify junctional disruption and autophagic flux, and assess whether genetic knockdown or pharmacologic inhibition of IRE1Α can rescue barrier integrity. Aim 2 will extend these studies in vivo by inducing systemic fever in mice and mapping barrier disruption across laminar and d-flow regions using advanced vascular imaging, while testing whether IRE1Α inhibition restores junctional integrity. This project is innovative in its dual-stressor paradigm and mechanistic focus on IRE1Α-XBP1-dependent autophagy as a convergence point between thermal and hemodynamic stress. The investigative team brings complementary expertise in mechanobiology (salinas), microsurgery and imaging (shindo), and cardiovascular pharmacology (speth). Conducted at nova southeastern university, a sure-eligible institution, this work will advance vascular biology while strengthening institutional research capacity. A defining feature is its integration of undergraduate training: each year, two students will participate in experimental design, execution, and data analysis, completing collaborative institutional training initiative (citi) and institutional animal care and use committee (iacuc) training, maintaining reproducibility standards, and contributing to abstracts and manuscripts. We expect 70 percent of participants to present their work and 50 percent to achieve CO-authorship, embedding a culture of rigor and dissemination. By revealing when, where, and how fever amplifies vascular leak at disturbed-flow sites, this project will establish a tractable pathway for intervention in febrile vascular injury while directly fulfilling the sure program's mission to build sustainable undergraduate research capacity and prepare the next generation of biomedical scientists.