Neural programming of mesenteric and renal arteries

Area of Science:

• Physiology
• Developmental Biology
• Vascular Biology

Background:

• Vascular smooth muscle (VSM) maturation is critical for regional circulation function, but its developmental origins remain poorly understood.
• Understanding the maturation of mesenteric small resistance arteries (SRAs) is key to explaining vascular dysfunction.
• The role of the sympathetic nervous system (SNS) in programming vascular development is an area requiring further investigation.

Purpose of the Study:

• To investigate maturational changes in VSM gene expression and myosin phosphatase (MP) in mesenteric SRAs.
• To determine the role of the SNS in programming mesenteric SRA function.
• To define the function of MP isoforms in the maturation of the mesenteric circulation using genetically engineered mice.

Main Methods:

• Quantitative PCR (qPCR) and immunoblotting to assess gene and protein expression during SRA maturation in rats.
• Ex vivo functional assays of mesenteric arteries to measure force production and calcium sensitization.
• Genetic manipulation in mice (conditional deletion of Mypt1 E24) to study MP isoform function.
• Neonatal chemical sympathectomy (6-hydroxydopamine) and mechanical denervation to assess SNS influence.

Main Results:

• Mesenteric SRA maturation begins postnatally, characterized by increased VSM differentiation markers, CPI-17, and adrenergic receptors.
• Functional maturation includes enhanced α-adrenergic force and calcium sensitization, linked to MP inhibition.
• The Mypt1 E24+/LZ- isoform is upregulated during maturation, and its splicing affects cGMP-mediated vasorelaxation.
• SNS signaling is essential for SRA maturation, as sympathectomy suppresses development, while denervation of mature arteries reverts gene expression.

Conclusions:

• The SNS plays a critical role in programming the maturation of mesenteric SRAs.
• Maturation involves coordinated changes in VSM gene expression, MP activity, and receptor signaling.
• SNS-mediated programming ensures appropriate vascular smooth muscle function in the mesenteric circulation.