{"doi":"10.1177/2045894020905508","title":"Anatomic, genetic and functional properties of the retinal circulation in pulmonary hypertension","abstract":"Pulmonary arterial hypertension (PAH) is a disease characterized by progressive loss and remodeling of the pulmonary arteries resulting in right heart failure and death. The majority of research has focused on endothelial dysfunction in the pulmonary circulation without much attention to whether similar pathology may be found in the rest of the circulatory system. However, there is growing evidence that PAH patients also exhibit systemic endothelial dysfunction as evidenced by impaired brachial artery flow-mediated dilation, abnormal cerebral blood flow and intrinsic kidney disease. Besides abnormalities in vascular function and metabolic processes, patients with systemic sclerosis and PAH have been reported to exhibit distinctive morphological changes in kidney, skin, nailfold capillaries and sublingual vessels.1 The eye is a highly vascularized organ that is sensitive to systemic changes in oxygen and blood flow. Interestingly, abnormally dilated episcleral vessels were found not only in PAH patients but also in unaffected carriers before the development of the disease. A more recent study by Chyou and colleagues using the Multi-Ethnic Study of Atherosclerosis database demonstrated that a higher right ventricular mass and volume by MRI correlated with a wider diameter in retinal vessels in women compared to men independent of body size, diabetes mellitus, cholesterol, age and alcohol use.2 While this study did not involve PAH patients, it is does allow speculation of a physiological communication between the retina and cardiopulmonary system that should be further explored. We sought to characterize the genetic and functional properties of human retinal endothelial cells (REC) along with anatomic characterization of healthy and PAH retinal vessels in human and a hypoxia mouse model of pulmonary hypertension (PH). Loss of function mutations in BMPR2 are the most common genetic cause of PAH and are associated with loss of endothelial viability and reduced angiogenesis.3 Interestingly, the presence of abnormal episcleral vessels has been documented in a family of BMPR2 mutations carriers, raising the possibility that BMPR2 loss could also affect the endothelial function of ocular vessels.4 To test this, we used siRNA to knockdown BMPR2 in healthy RECs and compared their capacity to form tube like structures in a Matrigel assay against pulmonary microvascular (PMV) ECs transfected in a similar fashion. We found that both siBMPR2 RECs and PMVECs displayed significantly reduced tube formation compared to cells transfected with a nontargeting siRNA Control (siCtrl, Fig. 1a). As a next step, we sought to identify the gene expression profile of siBMPR2 RECs and compare against that of healthy RECs and siBMPR2 PMVECs using the Angiogenesis RT2 Profile™ platform (cat #PAHS-024Z, Qiagen). Interestingly, angiogenesis cytokine profiles were more similar between RECs siBMPR2 and PMVECs siBMPR2 as evidenced by a close clustering in the ClusterGram heatmap (Supplement Fig. 1). This raises the possibility that RECs in patients with BMPR2 mutation may share similar angiogenesis gene profiles with PMVECs. BMPR2 knockdown is associated with reduced tube formation in both RECs and PMVECs. (a) Matrigel tube formation assay of PMVECs and RECs transfected with either control (siCtr) or BMPR2 specific siRNA (siBMPR2). **P < 0.001, unpaired t-test. (b) Retina vasculature of normoxia (left) and hypoxic (right) male C57BL6J mice. Retinal vessel area and branch points were measured with AngioTools. *P < 0.01, unpaired t-test. N = 4 mice per group. (c) Conventional funduscopic examination and AOSLO of healthy individual and two PAH patients. Notice tortuosity of vessels in PAH patient, highlighted in greater detail using AOSLO. Table 1 demonstrates genes that were >3-fold differentially regulated in siBMPR2 versus siCtrl RECs. Interestingly, the gene with the highest upregulation (8.18-fold) in siBMPR2 RECs was CXCL10, which codes for an angiostatic and p","journal":"Pulmonary Circulation","year":2020,"id":73457,"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":12,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9611,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":386179,"name":"Elya A. Shamskhou","orcid":"0000-0002-9188-6374","position":1,"is_corresponding":false},{"id":386852,"name":"Moataz A. Razeen","orcid":null,"position":2,"is_corresponding":false},{"id":386180,"name":"David Condon","orcid":"0000-0001-8073-8467","position":3,"is_corresponding":false},{"id":386853,"name":"Louise A. Messentier Louro","orcid":null,"position":4,"is_corresponding":false},{"id":278862,"name":"Alfredo Dubra","orcid":"0000-0002-6506-9020","position":5,"is_corresponding":false},{"id":5643,"name":"Yaping Joyce Liao","orcid":"0000-0001-7958-291X","position":6,"is_corresponding":false},{"id":92046,"name":"Roham T. Zamanian","orcid":"0000-0002-0734-0994","position":7,"is_corresponding":false},{"id":386181,"name":"Ke Yuan","orcid":"0000-0002-0458-3683","position":8,"is_corresponding":false},{"id":92047,"name":"Vinicio A. de Jesús Pérez","orcid":null,"position":9,"is_corresponding":false},{"id":386178,"name":"Nils Nickel","orcid":"0000-0002-8087-0166","position":0,"is_corresponding":true}],"reference_count":13,"raw_metadata":null,"created_at":"2026-07-18T21:45:32.034078Z","pmid":"32426109","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":[]}