Angiogenesis: A critical determinant for cardiac regeneration

Mammalian hearts during early post-natal life are resistant to any insults due to their ability to regenerate and restore cardiac function. This phenomenal response is absent in the adult heart, leading to maladaptive function and eventually heart failure. Cardiac regeneration is a cumulative effect of cardiomyocyte proliferation, extracellular matrix remodeling, immune response, nervous innervation, and angiogenesis (Figure 1).^1,2 Angiogenesis is very crucial for cardiac regeneration as they are vital for the supply of nutrients and oxygen. In a model of cardiac apical resection, vessels were formed just after 2 days of resection and acted as a guide for cardiomyocyte migration and proliferation in the resected area.³ Similarly, in a model of neonatal myocardial infarction, neovascularization was evident with the appearance of large collateral vessels in the infarcted area.⁴ Moreover, macrophages, which are necessary for cardiac regeneration post-myocardial infarction in neonates, were found to secrete stimulus for neoangiogenesis.⁵ Apart from these animal models of heavy cardiomyocyte loss like apical resection and myocardial infarction, angiogenesis has been recently shown to be critical for regenerative response to pressure overload in neonatal mice.⁶ Neonatal mice undergoing pressure-overload surgery in the regenerative phase have increased vascularization response and preserved cardiac function.⁶ On the contrary, pressure overload during the non-regenerative phase showed no changes in angiogenic response and declined cardiac function.⁶ Moreover, pharmacological blockage of angiogenesis by PTK787, a functional inhibitor of VEGFR2, exhibited decreased cardiomyocyte proliferation and cardiomyocyte hypertrophy and increased fibrosis, revealing that angiogenesis was a prerequisite for cardiomyocyte proliferation and adaptation following pressure overload.⁶ These results confirm an indispensable role of angiogenesis during neonatal cardiac regeneration.

Figure 1.

Circular RNAs as regulators of the neonatal cardiac regenerative process

Cardiac regeneration in neonatal hearts post apical resection, myocardial infarction, and pressure overload involve cardiomyocyte proliferation, angiogenesis, nervous innervation, immune modulation, and extracellular matrix remodeling. Circular RNAs circHipk3 and circNfix regulate cardiomyocyte proliferation. CircErbb2ip and circHipk3 regulate angiogenic response.

Similar to other cellular processes, cardiac regeneration is regulated by coding and non-coding RNAs. Non-coding RNAs act as regulatory RNA molecules at the transcriptional and post-transcriptional levels, and recent studies have demonstrated their critical role in cardiac regeneration.⁷ With the recent advancement in RNA sequencing techniques and analysis tools, a novel class of non-coding RNAs called circular RNAs has been identified.⁷ Circular RNAs are characterized by their circular nature formed due to RNA back splicing. Recently, circular RNAs have been demonstrated to play an active role in neonatal cardiac regeneration (Figure 1). circHipk3 was found to promote cardiomyocyte proliferation and angiogenesis, and its knock down in neonates undergoing myocardial infarction led to incomplete regeneration evident by decreased proliferation, increased apoptotic cells, increased fibrosis, and declined cardiac function.⁸ Moreover, circNfix, another highly abundant circular RNA in the adult heart, was found to inhibit cardiac regeneration.⁹ Mice with CRISPR-Cas9-mediated knock down of circNfix exhibited increased cardiomyocyte proliferation.⁹ On the contrary, overexpression of circNfix diminished cardiac regenerative potential in the infarcted neonatal heart.⁹ In the current issue of Molecular Therapy - Nucleic Acids, Long et al. have demonstrated a novel function for a circular RNA circErbb2ip in neonatal cardiac regeneration (Figure 1).¹⁰

circErbb2ip was highly expressed during the regenerative phase (post-natal day 1 [P1] neonate hearts) compared with the non-regenerative phase (P7 neonate and adult hearts).¹⁰ Long et al. demonstrated that inhibition of circErbb2ip in the neonatal heart prevented cardiac regeneration in response to myocardial infarction.¹⁰ Of note, declined regenerative potential upon circErbb2ip inhibition was mainly due to a reduction in angiogenic response, while cardiomyocyte proliferation remained unaltered,¹⁰ thus confirming the indispensable role of angiogenesis in cardiac regeneration. Besides neonatal heart, circErbb2ip was found to induce angiogenesis and improve cardiac function in adult mice hearts after myocardial infarction.¹⁰ This angiogenic function of circErbb2ip was mediated by targeting miR-145a-5p followed by derepression of the miR-145a-5p target Smad5.¹⁰ circErbb2ip was found to be induced by Gata4, a transcription factor well known to be crucial for neonatal cardiac regeneration. However, the detailed mechanism of circular RNA induction by transcription factors remains to be elucidated.

In conclusion, Long et al. have demonstrated that circErbb2IP is an important inducer of angiogenesis during cardiac regeneration and could be of therapeutic relevance to promote cardiac regeneration (Figure 1). However, cardiac regeneration is a multi-factorial process, and strategies aiming at the induction of a single process alone to boost it would not be efficiently translated. Therefore, to target cardiac regeneration as therapeutics, strategies addressing cardiomyocyte proliferation together with increased angiogenesis, immune modulation, and nervous innervation would be a better approach.