Dysfunctions of the C-type natriuretic peptide signaling pathway involved in the development of thoracic aortic aneurysm in Marfan patients

Abstract

Marfan Syndrome (MFS) is an autosomal dominant inherited connective tissue disorder affecting the cardio-vascular system. Development of thoracic aortic aneurysms (TAA) leading to dissections and ruptures is the primary cause of morbidity and mortality in these patients. No treatment really cures Marfan patients. Interestingly, in humans, mutations in the gene coding for the C-type natriuretic peptide (CNP) or its receptors lead to a “Marfan-like syndrome”. CNP is a local regulator of skeletal growth and of vascular homeostasis, remodeling and angiogenesis. CNP binds to NPR-B or NPR-C receptors, both expressed on endothelial and vascular smooth muscle cells (vSMCs) and modulates the intracellular cGMP and cAMP levels. The aim of this project is to determine whether altered CNP signaling pathway contributes to TAA development and progression to rupture in Marfan patients. Plasma and aorta biopsies were taken from Marfan patients and from Fbn1C1039G/+ mice. The CNP, TGF-beta, cAMP and cGMP concentrations were measured in the plasma. mRNA and protein levels evaluated by qRT-PCR, and Western blot analysis in aortic tissue. Male and female mice studied and alterations of the aorta structure analyzed by ultrasound imaging. Plasma proCNP level in Marfan patients depends on the age and the TAA development. Increased levels found in young patients presenting no or reduced TAA and decreased levels in patients with TAA compared to age and sex-matched non-Marfan patients. CNP and NPR-C decreased at the mRNA and protein levels in the aorta of Marfan patients when compared to the same aorta in non-Marfan patients. In Fbn1+/- mice, aortic structure alterations are detected from 10 weeks in males and 34 weeks in females. CNP and NPR-C mRNA and protein levels drastically decreased in the thoracic aorta in 2–7 week-old male mice and in 34 week-old female mice. In 52-week old Fbn1+/- mice, the plasma cAMP level is increased in males and not in females, whereas the plasma cGMP protein level is increased in females but not in males. CNP injections in 3-week old Fbn1+/- male mice partially prevented the aorta structure alterations. A deficit in CNP protein level or in the expression of the NPR-C receptor contributes to the development and progression of TAA.