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Arteries and veins develop different types of occlusive diseases and respond differently to injury. The biological reasons for this discrepancy are not well understood, which is a limiting factor for the development of vein-targeted therapies. This study contrasts human peripheral arteries and veins at the single-cell level, with a focus on cell populations with remodeling potential. Upper arm arteries (brachial) and veins (basilic/cephalic) from 30 organ donors were compared using a combination of bulk and single-cell RNA sequencing, proteomics, flow cytometry, and histology. The cellular atlases of six arteries and veins demonstrated a 7.8× higher proportion of contractile smooth muscle cells (SMCs) in arteries and a trend toward more modulated SMCs. In contrast, veins showed a higher abundance of endothelial cells, pericytes, and macrophages, as well as an increasing trend in fibroblasts. Activated fibroblasts had similar proportions in both types of vessels but with significant differences in gene expression. Modulated SMCs and activated fibroblasts were characterized by the upregulation of MYH10, FN1, COL8A1, and ITGA10. Activated fibroblasts also expressed F2R, POSTN, and COMP and were confirmed by F2R/CD90 flow cytometry. Activated fibroblasts from veins were the top producers of collagens among all fibroblast populations from both types of vessels. Venous fibroblasts were also highly angiogenic, proinflammatory, and hyper-responders to reactive oxygen species. Differences in wall structure further explain the significant contribution of fibroblast populations to remodeling in veins. Fibroblasts are almost exclusively located outside the external elastic lamina in arteries, while widely distributed throughout the venous wall. In line with the above, ECM-targeted proteomics confirmed a higher abundance of fibrillar collagens in veins vs. more basement ECM components in arteries. The distinct cellular compositions and transcriptional programs of reparative populations in arteries and veins may explain differences in acute and chronic wall remodeling between vessels. This information may be relevant for the development of antistenotic therapies.

Abstract Cardiovascular diseases are the principal cause of death worldwide, with hypertension being the most common cardiovascular disease risk factor. High blood pressure (BP) is also associated with an increased risk of poor cognitive performance and dementia including Alzheimer's disease. Angiotensin 1–7 (Ang 1‐7), a product of the renin‐angiotensin system (RAS), exhibits central and peripheral actions to reduce BP. Recent data from our lab reveals that the addition of a non‐radioactive iodine molecule to the tyrosine in position 4 of Ang 1‐7 (iodoAng 1‐7) makes it ~1000‐fold more potent than Ang 1‐7 in competing for the 125I‐Ang 1‐7 binding site (Stoyell‐Conti et al., 2020). Moreover, the addition of the non‐radioactive iodine molecule increases (~4‐fold) iodoAng 1‐7’s ability to bind to the AT1 receptor (AT1R), the primary receptor for Ang II. Preliminary data indicates that iodoAng 1‐7 can also compete for the 125I‐Ang IV binding site with a low micromolar IC50. Thus, our aims were to compare the effects of chronic treatment of the Spontaneously Hypertensive Rat (SHR) with iodoAng 1‐7 (non‐radioactive iodine isotope) and Ang 1‐7 on arterial pressure, heart rate, and cognitive function. For this study, male SHRs were divided into three groups and treated with Saline, Ang 1‐7, or iodoAng 1‐7 administrated subcutaneously using a 28‐day osmotic mini pump. Systolic BP was measured non‐invasively by the tail‐cuff technique. Cognitive function was assessed by Y‐Maze test and novel object recognition (NOR) test. We have demonstrated in SHRs that subcutaneous administration of high doses of iodoAng 1‐7 prevented the increase in heart rate with age, while Ang 1‐7 showed a trend toward preventing the increase in heart rate, possibly by improving baroreflex control of the heart. Conversely, neither Ang 1‐7 nor iodoAng 1‐7 administered subcutaneously affected BP nor cognitive function.

Angiotensin II analogue and β-arrestin biased agonist TRV027 (Sarcosine 1 , d-Alanine 8 -Angiotensin (Ang) II; SD Ang II), developed by Trevena, Inc. in the early 2010s, brought hopes of a novel treatment for cardiovascular diseases, due to its ability to simultaneously cause signaling through the β-arrestin signaling pathway, while antagonizing the pathophysiological effects of Ang II mediated by the AT 1 receptor G protein signaling cascades. However, a phase II clinical trial of this agent revealed no significant benefit compared to placebo treatment. Using 125 I-Sarcosine 1 , Isoleucine 8 -Ang II ( 125 I-SI Ang II) radioligand receptor competition binding assays, we assessed the relative affinity of TRV027 compared to SI Ang II for liver AT 1 receptors. We also compared radioiodinated TRV027 ( 125 I-SD Ang II) binding affinity for liver AT 1 receptors with 125 I-SI Ang II. We found that despite its anticipated gain in metabolic stability, TRV027 and 125 I-SD Ang II had reduced affinity for the AT 1 receptor compared with SI Ang II and 125 I-SI Ang II. Additionally, male-female comparisons showed that females have a higher AT 1 receptor density, potentially attributed to tissue-dependent estrogen and progesterone effects. Peptide drugs have become more popular over the years due to their increased bioavailability, fast onset of action, high specificity, and low toxicity. Even though Trevena®'s biased agonist peptide TRV027 offered greater stability and potency compared to earlier AT 1 R biased agonists, it failed its phase II clinical trial in 2016. Further refinements to AT 1 R biased agonist peptides to improve affinity, as seen with SI Ang II, with better stability and bioavailability, has the potential to achieve the anticipated biased agonism., (© 2023 The Authors. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)