# Cyclic nucleotide gradients regulate the balance of mechanical forces underlying pulmonary endothelial barrier integrity

> **NIH NIH P01** · UNIVERSITY OF SOUTH ALABAMA · 2020 · $357,648

## Abstract

PROJECT SUMMARY
Pulmonary microvascular endothelial cells (PMVECs) form contiguous, semi-permeable barriers between the
bloodstream and the interstitial space. cAMP generated by plasma membrane-localized adenylyl cyclases
(ACs) enhances PMVEC barriers. In contrast, cytosolic cAMP, cGMP, and cUMP generated by exogenous and
endogenous soluble cyclases disrupt PMVEC barriers. These observations suggest that cyclic nucleotide
signals are highly localized, or compartmentalized, and that near-membrane and cytosolic cAMP, cGMP, and
perhaps cUMP signals have opposing effects on endothelial function in the lung microvasculature. The concept
of compartmentalized signals implies that feedback networks localized to specific subcellular domains control
the kinetics of second messenger signals. However, our understanding of the physiological and
pathophysiological implications of localized feedback networks within pulmonary endothelial cells is at best
rudimentary. Thus, the overall goal of this project is to determine the spatial and temporal relationships
between compartmentalized cAMP signals, PKA-mediated feedback networks, and regulation of mechanical
forces in pulmonary endothelial cells. Experiments described in this proposal will for the first time identify
where cAMP signals occur in the 3D space of PMVECs, identify important temporal components of cAMP
signals, and chart feedback mechanisms contributing to signal localization and kinetics of these signals. In
other words, we will provide roadmaps identifying the spatial locations of cAMP signals that are critical for
controlling the dynamics of cellular forces. We will then overlay these responses onto PKA activity maps and
underlying distributions of A kinase anchoring proteins (AKAPs). As such, successful completion of the studies
proposed in this application will identify the spatial and temporal fingerprints of specific cAMP signalosomes
that regulate mechanical forces within pulmonary endothelial cells, and thus control endothelial barrier integrity.
The spatial and temporal fingerprints will direct future studies aimed at identifying target proteins within these
signalosomes, leading to both a better understanding of the molecular mechanisms underlying localized signal
transduction and identifying translational targets within signalosomes.

## Key facts

- **NIH application ID:** 9962991
- **Project number:** 5P01HL066299-18
- **Recipient organization:** UNIVERSITY OF SOUTH ALABAMA
- **Principal Investigator:** THOMAS C RICH
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $357,648
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9962991

## Citation

> US National Institutes of Health, RePORTER application 9962991, Cyclic nucleotide gradients regulate the balance of mechanical forces underlying pulmonary endothelial barrier integrity (5P01HL066299-18). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9962991. Licensed CC0.

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