Expanding clones, expanding aneurysms through macrophage-to-osteoclast differentiation

Area of Science:

• Cardiovascular Medicine
• Hematology
• Aging Research

Background:

• Abdominal aortic aneurysms (AAAs) are a significant cause of cardiovascular disease (CVD) morbidity and mortality, with limited non-surgical treatment options.
• Clonal hematopoiesis (CH), the age-related expansion of somatic clones in blood cells, is increasingly recognized as a factor in age-related diseases.

Purpose of the Study:

• To investigate the role of clonal hematopoiesis (CH) as a driver of abdominal aortic aneurysm (AAA) pathobiology.
• To explore the potential of targeting CH-associated mechanisms for AAA treatment.

Main Methods:

• Analysis of CH prevalence in AAA patients.
• Utilizing an angiotensin II-induced mouse model of AAA with ten-eleven translocation 2 (Tet2) mutations (Tet2-CH).
• Investigating macrophage reprogramming and targeting the RANK/RANKL pathway with FDA-approved therapies.

Main Results:

• Higher prevalence of CH in patients with AAA.
• CH carriers exhibited faster AAA expansion over one year.
• Tet2-CH mice showed accelerated AAA development and macrophage-to-osteoclast differentiation.
• Inhibition of RANK/RANKL signaling suppressed aneurysmal growth.

Conclusions:

• Age-related CH promotes AAA progression through macrophage-to-osteoclast differentiation.
• Targeting the RANK/RANKL pathway with existing therapeutics (alendronate, denosumab) can suppress AAA growth.
• This study identifies a novel, modifiable mechanism linking CH to AAA pathogenesis.