[Renin-angiotensin system and vascular remodelling]

Area of Science:

• Cardiovascular Physiology
• Molecular Biology
• Endocrinology

Background:

• The renin-angiotensin system (RAS) is compartmentalized, with circulating and tissue-bound components influencing cardiovascular health.
• Angiotensin II, a key peptide in the RAS, exerts localized effects within specific tissue compartments.
• Understanding RAS compartmentalization is crucial for deciphering its role in cardiovascular pathologies.

Purpose of the Study:

• To elucidate the distinct roles of circulating versus tissue-bound RAS components in vascular remodeling.
• To investigate the signaling pathways and cellular targets of angiotensin II in various cardiovascular diseases.
• To evaluate the therapeutic potential of angiotensin II antagonists in mitigating pathological vascular remodeling.

Main Methods:

• Analysis of renin-binding mechanisms and angiotensin-converting enzyme induction in vivo.
• Investigation of angiotensin II/AT1 receptor interactions and downstream signaling in target cells.
• Assessment of NADPH oxidase-derived reactive oxygen species and NF-kappaB activation in pathological responses.
• Evaluation of angiotensin II's role in hypertension, diabetes-related fibrosis, and experimental atherosclerosis.
• Testing the efficacy of angiotensin II antagonists in preclinical models of vascular remodeling.

Main Results:

• Tissue-bound renin and induced converting enzyme are key determinants of RAS involvement in vascular remodeling.
• Angiotensin II triggers immediate calcium-dependent responses, hypertrophy, and late pro-inflammatory/pro-coagulant effects via NADPH oxidase and NF-kappaB.
• Interstitial angiotensin II primarily targets vascular smooth muscle cells and fibroblasts, while circulating angiotensin II affects endothelial cells and leukocytes.
• In diabetes, angiotensin II promotes fibrosis by inducing TGF-beta expression.
• Angiotensin II infusion in experimental atherosclerosis leads to aneurysm formation mediated by leukocytes.
• Angiotensin II antagonists demonstrated beneficial effects on pathological remodeling in experimental models.

Conclusions:

• The compartmentalization of the RAS significantly influences its pathological roles in vascular remodeling.
• Angiotensin II's diverse signaling pathways contribute to hypertension, fibrosis, and atherosclerosis.
• While angiotensin II antagonists show promise in experimental settings, their clinical efficacy in human pathological remodeling requires further investigation.