Causes of aorta stiffening

These are some notes on a 2022 Pierce review on aging related aorta stiffening. Some form of PEMF may address some of the various contributing factors. The Pierce review provides a background on a PEMF and aorta stiffening study.

Causes of aorta stiffening Pierce 2022

Pierce GL, Coutinho TA, DuBose LE, Donato AJ. Is It Good to Have a Stiff Aorta with Aging? Causes and Consequences. Physiology (Bethesda). 2022 May 1;37(3):154-173. PMC free paper

Must view image in the Pierce review.

Subheadings in this image have been supplemented with text from Pierce 2022 and ways in which PEMF may enhance or mitigate these influences.

The cellular mechanisms and modulators that influence aortic stiffness can be classified into five general categories: 

1. alterations in the extracellular matrix in the arterial wall
2. modulators of arterial tone (i.e., vasodilators vs. vasoconstrictors)
3. intrinsic vascular smooth muscle cell stiffness,
4. arterial calcification
5. glycosaminoglycans (GAGs).
6. Alterations in arterial smooth muscle tone can occur acutely or gradually, whereas the other four mechanisms are typically chronic changes that can take months or years to occur but may be influenced by a variety of lifestyle or physiological stressors or pathologies

1 alterations in the extracellular matrix in the arterial wall

Advanced glycation end products, also involves NF-κB

Advanced glycation end products (AGE) occur when aldehyde of sugars form Schiff base with nitrogen in proteins and lipid head groups.

“Glycation of collagen may cause them to form non enzymatic cross links that impact their turnover. AGE may bind to receptors for AGE (RAGE) that results in he transcription of pro-inflammatory and pro-oxidant genes. In addition, advanced glycation end products (AGEs), proteins or lipids that are formed from nonenzymatic glycation or oxidation after exposure to aldose sugars, accumulate in the vessel wall, leading to cross-links in extracellular matrix proteins with slow turnover rate (i.e., collagen I), and promote arterial stiffening. Furthermore, AGEs also bind to several different receptors for AGEs (RAGEs), which results in up regulation of the proinflammatory transcription factor nuclear factor-κB (NF-κB) and subsequently numerous pro-inflammatory and pro-oxidant genes that contribute to endothelial dysfunction.”

links to cartoons of signaling by NF-κB

• A cartoon illustrating LPS signaling to NF-κB nuclear translocation.
• A cartoon illustrating AGE signaling to NF-κB nuclear translocation.

In summary, AGE are perceived the same was as bacterial infection derived lipopoly saccharide. PEMF is said to be good for infections. Does the literature support PEMF reducing NF-κB?

2. vasodilation, PEMF and arterial tone

Nitric oxide NO and endothelin-1 (ET-1)  were given a paragraph of discussion in the Pierce review. The former relaxes vascular smooth muscle cells while the latter causes hem to contract and blood vessels to constrict. The whole basis of the Assisi radio frequency PEMF devices is to simulate Ca²⁺ release and binding to calmodulin which activates nitric oxide synthase. Nitric oxide activate guanylyl cyclase. cGMP activate protein kinase G which turns on myosin light chain phosphatase, which turns off smooth muscle myosin. Many PEMF companies claim their devices relax smooth muscle via this mechanism.

PEMF could seem to be a more on going therapy in this case.

3. vascular smooth muscle stiffness

The paragraph the Pierce review spent on this topic mostly concerned β₁-integrin. My dissertation research concerned interactions of smooth muscle proteins actin, calponin, filamin, and α-actinin. The underlying hypothesis is that these proteins are responsible for making turkey gizzards so rubbery and our arteries so viscoelastic. My then Boston based collaborator Jay Tang introduced the Chalovich Lab to a concept of strain hardening in which the introduction of calponin makes actin/α-actinin gels stronger in response to strain. (Leinweber 1999) I should add that I was in Boston to post doc in Kathleen Morgan’s lab. Morgan 2024 demonstrated that calponin 1 acts as an inhibitor of ERK activation and calcium sensitization. Kajuluri 2021 is a review from the Morgan Lab that describes cytoskeletal changes in the aging aorta. Click Fig 1 for a must see cartoon. Fig 2 describes the differences between young and old aortas.

My general feel for this one is that PEMF field strength and wave form might be everything to influence ionic interactions.

4. arterial calcification

Use of magnetic fields to de-calcify pipes has been addressed on this site. PEMF is known for bone healing as reviewed on this site. On this site a study of 7.5 Hz on osteoclasts has been presented. Matrix Gla-protein is thought to act as an inhibitor of bone formation. Matrix Gla-protein , osteocalcin, is quite a perplexing ~100 amino acid peptide that sequesters Ca²⁺. Glutamates may acquire additional negative charges by the action of vitamin K hydroquinone dependent the enzyme gamma-glutamyl carboxylase which transfers the carboxyl group from CO₂ to the gamma carbon of the glutamate side chain. The Assisi PEMF device is based on radio frequency PEMF facilitating the interaction of Ca²⁺ and calmodulin. Could PEMF facilitate the interaction of Ca²⁺ with osteocalcin? If so, would the PEMF need to targeted to the thoracic aorta rather than bone?

“Matrix Gla-protein (MGP) is a protein secreted by vascular smooth muscle cells and chondrocytes. In its inactivated form, unphospho-decarboxylated MGP (dp-ucMGP) is an inhibitor of vascular calcification by blocking osteogenic differentiation of vascular smooth muscle cells”

MGP is also a Ca²⁺ binding protein. Could the Assisi Loop also promote Ca2+ binding to it as it does to calmodulin?

5. glycosaminoglycans

These polysaccharides tend to be negatively charged. A direct quote from the Pierce 2021, GAGs “attract cations such as sodium from interstitial fluid into the arterial wall. This creates an osmotic gradient promoting water influx into regions of the arterial wall containing GAGs, which can increase tissue volume (arterial wall swelling) in the vascular media”

Could Lorentzian forces of PEMF set these cations to motion in such a way as to affect vascular stiffness?

immune cell infiltration

“Advancing age is associated with increases in T and B cells as well as macrophages in the perivascular adipose tissue of both the aorta and mesenteric vascular arcade.” From the Pierce 2022 review…

• Perivascular adipose tissue is part of the atherosclerosis process and hence there are many images on the Internet. White and Beige perivascular adipose tissue by Chang 2020 paints a picture of beige adipocytes containing mitochondria having positive effects on vascular smooth muscle.
• The Medical Dictionary definition of an arcade is an “anatomic structure or structures (especially a blood vessel) taking the form of a series of arches.” The PEMF for inflammation post made a feeble attempt to summarize the literature. . Image links to aorta and mesenteric arcades paint a different picture of what PEMF could be doing. Surely, circulation through such structures must be under exquisite control by smooth muscle tone.

Can PEMF contribute to the cytokine homing in and out perivascular fat and tortuous arcades? What about PEMF and mitochondria? One possible view of all of this is that very low frequency PEMF simply stirs things up in regions that co not get a lot of stirring.