Akt Signaling Pathways Shown to Be Critical for Maintenance of Adult Vasculature

Sustained Akt signaling is critical to maintaining the healthy vasculature of adults, suggests new preclinical research published in Nature Communications by a Cleveland Clinic-led investigative team.

Preservation of the adult vasculature has remained a mystery

Multiple dynamic pathways are involved in the embryonic development of the vasculature. Once formed, the vasculature is expected to be largely dormant so it can function as a safe interface between circulating blood and tissues.

Very little is known about how the functionality and integrity of established vasculature is preserved throughout the life span. The Akt signaling pathway is one of the major pathways activated during the development and postnatal expansion of vasculature, such as during tumor growth. The Akt/mTOR pathway controls endothelial Jagged1 expression and, thereby, Notch signaling that regulates maintenance of vascular smooth muscle cells (VSMCs). Hyperactivated Akt signaling is thought to contribute to several pathologic states, including cancer. Although Akt inhibitors are in clinical development for application in cancer therapy, the consequences of Akt inhibition in the clinical setting are still being investigated.

To assess the function of Akt signaling pathways in maintaining stability and homeostasis of the adult vasculature, Tatiana V. Byzova, PhD, and colleagues in the Department of Molecular Cardiology in Cleveland Clinic’s Lerner Research Institute conducted a variety of preclinical studies reported in the new Nature Communications paper.

Akt signaling inhibition proves detrimental to cardiac and retinal vasculature

Figure 1. Vascular abnormalities in the heart triggered by Akt deletion. Microcomputed tomography imaging confirmed the structural changes in arterial vasculature of wild-type (left) and Akt-knockout (right) mice after tamoxifen treatment. Reprinted from Kerr et al., Nat Commun (2016 Mar 14;7:10960), via a Creative Commons license.

In a mouse model assessing cardiac function, nearly complete inhibition of Akt signaling did not affect endothelial cell survival but led to the loss of VSMCs and, eventually, to deterioration of the coronary vasculature, impaired vascular patency in the heart and cardiac dysfunction. Microcomputed tomography imaging confirmed the structural changes in the arterial vasculature of the hearts from wild-type and Akt1 and Akt2 knockout models (Figure 1).

A similar result was observed in a model of retinal function in which inhibition of Akt signaling produced vascular regression and retinal atrophy (Figures 2 and 3). In some models, vascular regression and severe organ dysfunction occurred within four weeks of suppression of Akt signaling.

Figure 2. Changes in the retina after Akt deletion included vascular deterioration and marked loss of the basement membrane component, collagen IV. Representative images show whole-mount retinas stained for collagen IV (red) and isolectin B4 (green) from Akt1- and Akt2-knockout mice (8 to 9 weeks old) after tamoxifen treatment. Reprinted from Kerr et al., Nat Commun (2016 Mar 14;7:10960), via a Creative Commons license.

Figure 3. Representative images of whole-mount retinas from wild-type (WT) and three different Akt1-knockout mice (10-day neonates) after tamoxifen treatment. The retinas, stained for smooth muscle actin (green) and CD31 (red), demonstrate the stages of smooth muscle cell loss by blood vessels. Reprinted from Kerr et al., Nat Commun (2016 Mar 14;7:10960), via a Creative Commons license.

Taken together, the results suggest that sustained Akt signaling is critical in maintaining the healthy vasculature of adults. “Akt signaling in endothelium does not simply preserve a barrier between the blood and the vessel wall, but serves as a guardian of vascular stability,” says Dr. Byzova. Her team also found that the function of Akt in established vasculature appears to be distinct from the role of Akt during embryonic development.

“These findings are unique in regard to endothelial function,” Dr. Byzova notes. “They are also unique because they show that this pathway needs to be active to keep the vasculature together and practically nothing is known about requirements to maintain healthy and functional adult vasculature.”

Implications for clinical development of Akt inhibitors

The researchers concluded that these new studies demonstrate that Akt signaling pathways are involved in the maintenance of vascular stability and homeostasis in adults. Given the role of Akt signaling in preserving tissue and organ function, complete inhibition of Akt signaling in the endothelium of adults may have detrimental effects on tissues and cardiac function.

“Not only might the inhibition of both isoforms, Akt1/Akt2, affect cancer and its vasculature, but it also might diminish the function of normal blood vessels, thereby causing side effects,” explains Dr. Byzova. “These findings imply that development of more-specific Akt inhibitors may maximize their efficacy while minimizing side effects.”

As part of an ongoing research program, she and her colleagues continue to explore new pathways preserving normal vascular function in various diseases and how these pathways might be affected by anticancer therapies.