Targeting dys‐regulated mechano‐transduction mechanisms in treating arterial and pulmonary vascular diseases by nanomedicine
Authors: Fang Yun , Huang Ru‐Ting , Wu David , Oh Myung‐Jin , Leon Lorraine , Mutlu Gokhan , Tirrell Matthew 
Published: November 2023

Objective

Mechanical stimuli regulate major cellular functions and play critical roles in the pathogenesis of diverse human diseases. This is especially important in the vasculature, where endothelial cells are activated by local disturbed flow in arterial regions prone to atherosclerosis or stimulated by excessive lung stretching leading to ventilator‐induced lung injury. Our studies aim to discover new mechano‐transduction mechanisms in vascular endothelium and further develop nanomedicine‐based approaches to treat diseased vasculatures in cardiovascular and pulmonary diseases.

Methods

In vitro and in vivo models in combinations with approaches of human genetics, high‐throughput sequencing, bioinformatics, and bioengineering systems, were used to systematically investigate endothelial responses to pathological mechanical stimuli such as disturbed flow and 18% cyclic stretch related to atherosclerosis and ventilator‐induced lung injury, respectively. Moreover, innovative nanoparticles were engineered to target dys‐regulated endothelial mechano‐transduction mechanisms in animal models of atherosclerosis and acute lung injury.

Results

Our animal and in vitro results identified novel molecular mechanisms contributing to endothelial dysfunction related to atherosclerosis and acute lung injury. Disturbed flow led to reduction of endothelial PPAP2B, a coronary artery disease‐associated gene identified by genome‐wide association studies (GWAS), through a miR92a‐mediated mechano‐transduction pathway. Reduced endothelial PPAP2B caused increased lysophosphatidic acid (LPA) signaling, resulting in elevated endothelial inflammation and compromised monolayer integrity. Meanwhile, pathological cyclic stretch resulted in inhibition of endothelial KLF2, a novel activator of small GTPase Rac1 by transcriptionally controlling RAPGEF3/EPAC1 that maintains vascular integrity. KLF2 also regulates multiple acute lung injury GWAS genes related to cytokine storm, oxidation, and coagulation in lung microvascular endothelium. Innovative polymeric nanoparticles were designed and engineered to specifically inhibit endothelial miR‐92a or restore lung KLF2 to treat atherosclerosis and acute lung injury, respectively. VCAM‐1 targeted nanoparticles successfully delivered miR‐92a inhibitors to inflamed endothelium activated by disturbed low and significantly reduced atherosclerotic burdens in apoe−⁄− mice. Moreover, over‐expression of KLF2 by lung‐targeted nanoparticles notably ameliorated LPS‐induced lung injury in mice.

Conclusions

Our data elucidate novel endothelial mechano‐transduction mechanisms related to genome‐wide association studies of coronary artery disease and acute lung injury. Inhibition of endothelial mechano‐transduction mechanisms induced by disturbed flow or pathological cyclic stretch by targeted nanoparticles significantly ameliorates atherosclerosis and acute lung injury, respectively in animal models.

Support or Funding Information

National Institutes of Health and American Heart Association