{"doi":"10.1161/atvbaha.124.321334","title":"Targeting Vascular Stiffness","abstract":"Artery stiffening, a biomechanical vascular property closely related to, but separate from hypertension, is a strong and independent cardiovascular disease risk factor that also predicts end organ failure. [1][2]2][3] Decreased aortic compliance elevates the mechanical load on the myocardium, increases peripheral pulse-pressure in the microvasculature resulting in tissue damage in high flow organs such as the brain and kidneys, and contributes to atherosclerotic plaque formation and progression by altering mechanical stress signaling within the vessel wall.In addition to hypertension, many cardiovascular risk factors including aging, smoking, inflammation and obesity have been associated with vessel stiffening.However, difficulties in isolating vascular stiffness as a variable in experimental models [4][5][6] has made it challenging to determine the molecular mechanisms that drive its progression.Although decreases in aortic compliance were originally thought to be mediated by changes in extracellular matrix content and composition (i.e.elastin degradation, collagen deposition, etc.) it has now become clear that the intrinsic mechanical properties of vascular SMC also play a role 7, 8 .In the current edition of ATVB, Khoukaz and colleagues add to our understanding of the signaling mechanisms that influence vessel stiffening and provide evidence that inhibition of Plasminogen Activator Inhibitor-1 (PAI-1) may be an effective therapeutic strategy 9 .In their studies, the PAI-1 inhibitor, PAI-039 (tiplaxtinin), decreased the stiffness of cultured human coronary SMCs as measured by atomic force microscopy and the stiffness of the abdominal aorta as measured by pulse wave velocity in mice fed a Western diet.These effects were accompanied by a decrease in F:G actin ratios and by activation (dephosphorylation) of Cofilin1, an Actin Depolymerizing Factor (ADF) downstream of the Rho subfamily of small GTPases.Although it is well known that Rho regulates cytoskeletal dynamics to control many biophysical cell properties and that Rho signaling enhances SMC contractility 10 and SMC-specific contractile gene expression 11 , these studies are among the first to provide direct evidence that actin polymerization in SMCs is a critical parameter of vascular stiffening and that Cofilin1-dependent actin severing may play a role.In support of these findings, Morales-Quinones and colleagues observed increased vascular stiffness, F:G actin ratios and Cofilin1 phosphorylation in human omental arteries isolated from hypertensive patients 12 .Fang and colleagues also recently demonstrated that the ability of the atypical GTPase, Rhobtb1, to decrease vessel stiffness was associated with a decrease in actin polymerization perhaps related to concomitant increases in Cofilin1 expression","journal":"Arteriosclerosis Thrombosis and Vascular Biology","year":2024,"id":486298,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9602,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":442230,"name":"Christopher P. Mack","orcid":"0000-0001-6713-0844","position":0,"is_corresponding":true}],"reference_count":25,"raw_metadata":null,"created_at":"2026-07-19T02:07:57.049469Z","pmid":"39114918","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}