Current Evidence and Future Perspectives in the Medical Management of Vascular Ehlers-Danlos Syndrome: Focus on Vascular Prevention

Abstract

Vascular Ehlers-Danlos syndrome (vEDS) is a rare autosomal dominant connective tissue disease resulting from pathogenic variants in the collagen type III alpha 1 chain (COL3A1) gene, encoding type III procollagen. Patients with vEDS present with severe tissue fragility that can result in arterial aneurysm, dissection, or rupture, especially of medium-caliber vessels. Although early reports have indicated a very high mortality rate in affected patients, with an estimated median survival of around 50 years, recent times have seen a remarkable improvement in outcomes in this population. This shift could be related to greater awareness of the disease among patients and physicians, with improved management both in terms of follow-up and treatment of complications. Increasing use of drugs acting on the cardiovascular system may also have contributed to this improvement. In particular, celiprolol, a β1 cardio-selective blocker with a β2-agonist vasodilator effect, has been shown to reduce rates of vascular events in patients with vEDS. However, the evidence on the true benefits and possible mechanisms responsible for the protective effect of celiprolol in this specific setting remains limited. Drugs targeting the extracellular matrix organization and autophagy-lysosome pathways are currently under investigation and could play a role in the future. This narrative review aims to summarize current evidence and future perspectives on vEDS medical treatment, with a specific focus on vascular prevention.

Keywords: celiprolol; gene therapy; non-coding RNA; pharmacological treatment; vascular Ehlers–Danlos syndrome; vascular prevention.

Figure 1

Potential therapeutic approaches to vascular Ehlers–Danlos syndrome. Celiprolol may reduce total peripheral resistance by dilating skeletal muscle resistance vessels through β2-adrenergic receptors and might decrease arterial wall shear stress by lowering heart rate through β1-adrenergic receptor antagonism. This drug could also reduce vascular oxidative stress at the arterial wall level by stimulating nitric oxide production. Lastly, it might increase arterial stiffness by enhancing TGFβ-mediated pro-fibrotic mechanisms and promoting collagen synthesis via β1 antagonism and β2 stimulation, respectively. By acting on angiotensin receptors, sartans could provide vascular protection either by inducing vasodilation or by limiting the adverse effects of angiotensin II on vascular remodeling. Targeting matrix metalloproteinases (MMPs) via doxycycline might counteract collagen degradation, thereby increasing its content in the arterial wall and enhancing vessel stiffness. Inhibition of phospholipase C/inositol 1,4,5-triphosphate/protein kinase C/extracellular signal-regulated kinase (PLC/IP3/PKC/ERK) has been shown to prevent spontaneous fatal aortic rupture in a mouse model. Antiandrogen medications may also contribute by interfering with this signaling pathway. Future research should identify drugs capable of improving mechanisms of autophagy, endoplasmic reticulum (ER) homeostasis, and stress response, which are likely to contribute substantially in the natural history of vEDS. Red lines: inhibition; green lines: stimulation; AR: androgen receptor; AT₁R: angiotensin 1 receptor; β₂AR: β2-adrenergic receptor; DHT: dihydrotestosterone; ECM: extracellular matrix; ER: endoplasmic reticulum; MMP: matrix metalloproteinase.